Substituted amide compound

ABSTRACT

A substituted amide compound is useful as an active ingredient of a pharmaceutical composition, in particular a pharmaceutical composition for treating diseases caused by lysophosphatidic acid (LPA). The compound is of a formula: 
     
       
         
         
             
             
         
       
     
     In this formula, A is an optionally substituted aryl, etc.; B is an optionally substituted 5-membered aromatic hetero ring group; X is a single bond or —(CR X1 R X2 ) n —; n is 1, 2, 3, or 4; R X1  and R X2  are hydrogen, etc.; Y 1  to Y 5  are each CR Y  or N; each R Y  is hydrogen, etc.; R 1  and R 2  are hydrogen, etc.; m is 1, 2, or 3; R 3  is hydrogen, etc.; and R 4  is an optionally substituted lower alkyl, etc.

TECHNICAL FIELD

The present invention relates to a substituted amide compound which isuseful as an active ingredient of a pharmaceutical composition, inparticular, a pharmaceutical composition for preventing and/or treatingdiseases caused by lysophosphatidic acid (hereinafter abbreviated asLPA).

BACKGROUND ART

LPA is a phospholipid, for example, as represented by the followingchemical formula, which has a simple structure containing a glycerolunit in which a fatty acid is present at the 1-position or 2-positionand a phosphate group is bonded at the 3-position. Examples thereofinclude 1-acyl LPA, 1-alkyl LPA, 1-alkenyl LPA, 2-acyl LPA, and thelike. Further, it has diversity depending on the type of the fatty acid,and may be classified into 18:1-LPA, 18:3-LPA, 16:0-LPA, and the likeaccording to the length of the carbon chain and the degree ofunsaturation.

It is known that LPA is produced in various parts of the living body,both inside and outside of the cells, transduces signals into the cellmainly by binding to a G-protein coupled receptor present on the cellsurface, and shows various physiological effects. 5 subtypes of LPAreceptors are known, LPA1 to LPA5. Among these, three types ofreceptors, LPA1, LPA2, and LPA3 are also known as EDG (EndothelialDifferentiation Gene)2, EDG4, and EDG7, respectively. The LPA receptorsare distributed in various parts in the living body, but thedistribution vary depending on the subtype, and it is thought that eachreceptor subtypes are involved in the biological functions of eachtissue.

It has been reported that LPA is present in the semen in the lowerurinary tract (Non-Patent Document 1), and it has been revealed that LPAinduces contraction of isolated urethral and prostate tissue strips invitro, and increases the urethral pressure in vivo (Patent Document 1).

Furthermore, it has been reported that LPA induces contraction ofisolated bladder smooth muscle cells, and LPA also promotes theproliferation of prostate cells obtained from benign prostatichyperplasia (Non-Patent Documents 2 and 3).

In the nerve cells, LPA1 is highly expressed in oligodendrocytes andSchwann cells in a myelination period, and is expressed incorrespondence with the period of myelination (Non-Patent Document 4).

It is also known that in a mouse model with demyelination, the amount ofmRNA of LPA1 decreases by about 40% (Non-Patent Document 5).

It has been suggested that LPA inhibits the cell death of Schwann cellsand oligodendrocytes, and is involved in the myelination (Non-PatentDocument 6).

It has further been reported that LPA and LPA 1 are involved in theexpression of neuropathic pain (Non-Patent Document 7).

It has been shown that LPA is involved in various fibrotic diseases. Ithas been reported that in hepatic fibrosis, LPA promotes the contractionand proliferation of stellate cells which play an important role in theprocess of hepatic fibrosis and that the LPA concentration increases inanimal models with chronic hepatitis C and various hepatic diseases(Non-Patent Documents 8, 9, 10, and 11). It has further been reportedthat in renal fibrosis, the production of LPA and the expression of LPA1increase in a mice with unilateral ureteral ligation model, which is ananimal model of renal fibrosis, and the progression of fibrosisdecreases in LPA 1-deficient mice and LPA receptor antagonists(Non-Patent Document 12). It has been reported that with respect topulmonary fibrosis, the LPA concentration in the bronchoalveolar lavagefluid in patients with idiopathic pulmonary fibrosis increases, that theLPA concentration in the bronchoalveolar lavage fluid increases in modelmice with bleomycin-induced lung fibrosis, and that the progression offibrosis and the death are remarkably inhibited in LPA 1-deficient mice(Non-Patent Document 13).

In addition, it has been reported that LPA is accumulated to mediate theactivation of platelets and endothelial cells by oxidized LDL inatherosclerosis lesions, and it has been suggested that LPA is involvedin cardiovascular diseases (Non-Patent Document 14).

Furthermore, it is known that in the proliferative diseases, LPApromotes the migration of cancer cells (Non-Patent Document 15). It hasbeen reported that the LPA concentration increases in the ascites ofpatients with ovarian cancer, and actually promotes the proliferation ofthe ovarian cancer cells (Non-Patent Documents 16 and 17). It has beenreported that in prostate cancer, the expression of LPA1 increases inthe tumorlesion and the proliferation is enhanced in the prostate cancercells overexpressing LPA1 (Non-Patent Document 18). It also has beenreported that in breast cancer bone metastasis models, overexpression ofLPA1 increases tumor proliferation/metastasi and LPA receptor antagonistinhibits the metastasis (Non-Patent Document 19). Further, in recentyears, it has been rapidly revealed that various cells surroundingcancer cells assist the survival, growth, and distant metastasis ofcancer cells in the cancer tissues. It has been revealed that humanfat-derived mesenchymal stem cells differentiate into tumor-associatedfibroblasts through the activation of LPA1 in tumor tissues bytransplantation with cancer cells, thereby promoting thegrowth/angiogenesis of tumors (Non-Patent Document 20).

From the findings obtained by various studies on the LPA and LPAreceptors, it is thought that an agent which inhibits the physiologicalactivity of LPA, in particular, an antagonist of LPA1, may be useful asa drug for preventing or treating urologic diseases such as urinarydisfunction associated with benign prostatic hyperplasia and the like,central/peripheral nervous system neurological diseases and urologicalnerve diseases, hepatitis and renal insufficiency, fibrotic diseasessuch as idiopathic pulmonary fibrosis and the like, cardiovasculardiseases such as atherosclerosis and the like, and proliferativediseases such as prostate cancer, breast cancer, ovarian cancer, and thelike.

Meanwhile, it is known that a carboxylic acid derivative represented bythe formula (A) has an LPA receptor antagonistic action and is usefulfor various diseases, for example, urinary system diseases,cancer-related diseases, proliferative diseases, inflammatory immunedisease, brain-related diseases, chronic diseases, and the like (PatentDocument 2).

(wherein Z represents an acidic group, for the others, refer to thepublication.)

It is further known that a compound represented by the formula (B) hasan LPA receptor antagonistic action and is useful for various diseases,for example, urinary system diseases (benign prostatic hyperplasia,neurogenic bladder diseases, and the like), cancer-related diseases,proliferative diseases, inflammatory immune diseases, brain-relateddiseases, chronic diseases, and the like (Patent Document 3).

(for the symbols in the formula, refer to the publication.)

In any of the documents above, there is no specific disclosure of thecompound of the present invention.

RELATED ART Non-Patent Document

-   [Non-Patent Document 1] EBS Lett. 2002, 523, 187.-   [Non-Patent Document 2] J. Urol. 1999, 162, 1779.-   [Non-Patent Document 3] J. Urol. 2000, 163, 1027.-   [Non-Patent Document 4] Eur. J. Neurosci. 1998, 10, 1045.-   [Non-Patent Document 5] J. Comp. Neurol. 1998, 398, 587.-   [Non-Patent Document 6] Proc. Natl. Acad. Sci. U.S.A. 1999, 96,    5233.-   [Non-Patent Document 7] Nat. Med. 2004, 10, 712.-   [Non-Patent Document 8] Biochem. Biophys. Res. Commun. 2000, 277,    72.-   [Non-Patent Document 9] Biochem. Biophys. Res. Commun. 2000, 248,    436.-   [Non-Patent Document 10] J. Clin. Gastroenterol. 2007, 41, 616.-   [Non-Patent Document 11] Life Sci. 2007, 81, 1009.-   [Non-Patent Document 12] J. Am. Soc. Nephrol. 2007, 18, 3110.-   [Non-Patent Document 13] Nat. Med. 2007, 14, 45.-   [Non-Patent Document 14] Proc. Natl. Acad. Sci. U.S.A. 1999, 96,    6931.-   [Non-Patent Document 15] Biochem. Biophysic. Res. Communic. 1993,    193, 497.-   [Non-Patent Document 16] JAMA 1998, 280, 719.-   [Non-Patent Document 17] J. Natl. Cancer. Inst. 2001, 93, 762.-   [Non-Patent Document 18] Endocrinology 2006, 147, 4883.-   [Non-Patent Document 19] Proc Natl Acad Sci U.S.A. 2006, 103, 9643.-   [Non-Patent Document 20] Biochim Biophys Acta. 2010, 1801, 1205.-   [Patent Document 1] Pamphlet of International Publication WO    02/062389-   [Patent Document 2] Pamphlet of International Publication WO    2004/031118-   [Patent Document 3] Pamphlet of International Publication WO    2005/058790

DISCLOSURE OF INVENTION Technical Problem Problems to be Solved by theInvention

The present invention provides a substituted amide compound which isuseful as an active component of a pharmaceutical composition, inparticular, a pharmaceutical composition for preventing and/or treatingdiseases caused by LPA.

Means for Solving the Problems

The present inventors have made intensive studies on a compound havingan antagonistic action against LPA receptor, and as a result, they havefound that a substituted amide compound which is the compound of thepresent invention has an excellent antagonistic action against LPAreceptor and is useful as an agent for preventing and/or treatingdiseases caused by LPA, thereby completing the present invention.

The present invention relates to a compound of the formula (I) or a saltthereof

(wherein A is an aryl which may be substituted or a hetero ring groupwhich may be substituted,

B is a 5-membered aromatic hetero ring group which may be substituted,

X is a single bond or —(CR^(X1)R^(X2))_(n)—,

n is 1, 2, 3, or 4,

R^(X1) and R^(X2) are the same as or different from each other, and areH, halogen, OH, —O-(lower alkyl which may be substituted), or loweralkyl which may be substituted, or

R^(X1) and R^(X2) are combined with each other to form oxo (═O), or

R^(X1) and R^(X2) are combined with each other to form C₂₋₅ alkylenewhich may be substituted,

in which when n is 2, 3, or 4, R^(X1) may be combined with adjacentR^(X1) to form a new bond,

Y¹, Y², Y³, Y⁴, and Y⁵ are the same as or different from each other, andare CR^(Y) or N,

R^(Y)'s are the same as or different from each other, and are H, OH,halogen, —O-(lower alkyl which may be substituted), —S-(lower alkylwhich may be substituted), lower alkyl which may be substituted, loweralkenyl which may be substituted, or cycloalkyl which may besubstituted,

R¹ and R² are the same as or different from each other, and are H,halogen, —O-(lower alkyl which may be substituted), or lower alkyl whichmay be substituted,

m is 1, 2, or 3,

R³ is H, or lower alkyl which may be substituted,

R⁴ is lower alkyl which may be substituted, lower alkenyl which may besubstituted, cycloalkyl which may be substituted, aryl which may besubstituted, a hetero ring group which may be substituted, or NR¹⁰¹R¹⁰²,or

R³ and R⁴ may be combined with each other to form C₂₋₅ alkylene whichmay be substituted, and

R¹⁰¹ and R¹⁰² are the same as or different from each other, and are H,OH, —O-(lower alkyl which may be substituted), —C(═O)-(lower alkyl whichmay be substituted), —C(═O)—O-(lower alkyl which may be substituted),—NH—C(═O)-(lower alkyl which may be substituted), lower alkyl which maybe substituted, lower alkenyl which may be substituted, cycloalkyl whichmay be substituted, aryl which may be substituted, or a hetero ringgroup which may be substituted, or R¹⁰¹ and R¹⁰² may be combined withnitrogen atoms to which they are bonded to form a nitrogen-containingmonocyclic saturated hetero ring group,

in which when R⁴ is NR¹⁰¹R¹⁰², at least one of R³, R¹⁰¹, and R¹⁰² is H.)

Moreover, unless specified otherwise, in the case where the symbols ofthe formulae in the present specification are also used in otherchemical formulae, the same symbols denote the same meanings.

The present invention relates to a pharmaceutical composition includingthe compound of the formula (I) or a salt thereof, and an excipient.

Furthermore, the present invention relates to pharmaceuticalcomposition, in particular, a pharmaceutical composition for preventingand/or treating diseases caused by LPA, which includes the compound ofthe formula (I) or a salt thereof, and an excipient.

In addition, the present invention relates to use of the compound of theformula (I) or a salt thereof for the preparation of a pharmaceuticalcomposition for preventing and/or treating diseases caused by LPA, useof the compound of the formula (I) or a salt thereof for preventionand/or treatment of diseases caused by LPA, the compound of the formula(I) or a salt thereof for prevention and/or treatment of diseases causedby LPA, and a method for preventing and/or treating diseases caused byLPA, including administering to a patient an effective amount of thecompound of the formula (I) or a salt thereof.

Effects of the Invention

The compound of the formula (I) or a salt thereof has an antagonisticaction against LPA receptor and can be used as an agent for preventingand/or treating diseases caused by LPA.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail. Further,“the compound of the formula (I) or a salt thereof” may be hereinafterdenoted as “the compound (I) of the present invention” or “the compound(I)” in some cases.

In the present specification, the “lower alkyl” refers to linear orbranched alkyl having 1 to 6 carbon atoms (which is hereinafter simplyreferred to as C₁₋₆), for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or thelike. In another embodiment, it is C₁₋₄ alkyl, and in a still anotherembodiment, C₁₋₃ alkyl.

The “lower alkenyl” refers to linear or branched C₂₋₆ alkenyl, forexample, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl,1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, or the like. Inanother embodiment, it is C₂₋₄ alkenyl, and in a still anotherembodiment, C₂₋₃ alkenyl.

The “lower alkynyl” refers to linear or branched C₂₋₆ alkynyl, forexample, ethynyl, propynyl, butynyl, pentynyl, 1-methyl-2-propynyl,1,3-butadiynyl, 1,3-pentadiynyl, or the like. In another embodiment, itis C₂₋₄ alkynyl.

The “alkylene” refers to linear or branched alkylene. The “C₂₋₅alkylene” means alkylene having 2 to 5 carbon atoms, for example,methylene, ethylene, trimethylene, tetramethylene, pentamethylene,propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, or thelike. Further, in another embodiment, it is C₂₋₄ alkylene, and in astill another embodiment, C₂₋₃ alkylene.

The “cycloalkyl” refers to a C₃₋₁₀ saturated hydrocarbon ring group,which may have a bridge. It is, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or thelike. In an embodiment, it is C₃₋₈ cycloalkyl, and in a still anotherembodiment, C₃₋₆ cycloalkyl.

The “aryl” includes a C₆₋₁₄ monocyclic to tricyclic aromatic hydrocarbonring group, and includes a ring group condensed with C₅₋₈ cycloalkene atits double bond site. It is, for example, phenyl, naphthyl,5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, or the like.

The “hetero ring” means a ring group selected from i) a monocyclic 3- to8-membered, and in another embodiment, a 5- to 7-membered hetero ring,containing 1 to 4 hetero atoms selected from oxygen, sulfur, andnitrogen, and ii) a bi- to tricyclic hetero ring containing 1 to 5hetero atoms selected from oxygen, sulfur, and nitrogen, formed bycondensation of the monocyclic hetero ring with one or two rings isselected from the group consisting of a monocyclic hetero ring, abenzene ring, C₅₋₈ cycloalkane, and C₅₋₈ cycloalkene. The ring atom,sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.

Examples of the “hetero ring” include the following embodiments.

(1) Monocyclic saturated hetero ring groups

(a) those containing 1 to 4 nitrogen atoms, for example, azepanyl,diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino,homopiperazinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atomsand/or 1 to 2 oxygen atoms, for example, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, oxazolidinyl, morpholinyl, and the like;

(c) those containing 1 to 2 sulfur atoms, for example,tetrahydrothiopyranyl and the like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, forexample, oxathiolanyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, oxiranyl,oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl,1,4-dioxanyl, and the like;

(2) Monocyclic unsaturated hetero ring groups

(a) those containing 1 to 4 nitrogen atoms, for example, pyrrolyl,2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl,pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl,azepinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atomsand/or 1 to 2 oxygen atoms, for example, thiazolyl, isothiazolyl,thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl,oxazinyl, and the like;

(c) those containing 1 to 2 sulfur atoms, for example, thienyl,thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl, andthe like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms,specifically, dihydroxathiopyranyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, furyl,dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl, and the like;

(3) Fused polycyclic saturated hetero ring groups

(a) those containing 1 to 5 nitrogen atoms, for example, quinuclidinyl,7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanyl, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atomsand/or 1 to 3 oxygen atoms, for example, trithiadiazaindenyl,dioxoloimidazolidinyl, and the like;

(c) those containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, forexample, 2,6-dioxabicyclo[3.2.2]oct-7-yl and the like;

(4) Fused polycyclic unsaturated hetero ring groups

(a) those containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolinyl, indolizinyl, benzoimidazolyl,dihydrobenzoimidazolyl, tetrahydrobenzoimidazolyl, quinolyl,tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl,imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl,acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl,phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl,quinazolinyl, cinnolinyl, pyridopyrrolidinyl, triazolopiperidinyl,9,10-dihydroacridine, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atomsand/or 1 to 3 oxygen atoms, for example, benzothiazolyl,dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl,imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl,dihydrobenzoxazinyl, benzoxadiazolyl, benzoisothiazolyl,benzoisoxazolyl, thiazolopiperidinyl,5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazol-2-yl, 10H-phenothiazine, andthe like;

(c) those containing 1 to 3 sulfur atoms, for example, benzothienyl,benzodithiopyranyl, chromanyl, dibenzo[b,d]thienyl, and the like;

(d) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, forexample, benzoxathiopyranyl, phenoxazinyl, and the like;

(e) those containing 1 to 3 oxygen atoms, for example, benzodioxolyl,benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl,chromenyl, isochromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl,ethylenedioxyphenyl, xanthenyl, and the like;

etc.

Further, the “hetero ring” in (1) to (4) above is described as amonovalent group, but this may represent a divalent or higher group insome cases.

The “monocyclic hetero ring” refers to a hetero ring which has no fusedring as in (1) and (2), among the “hetero rings” above.

The “nitrogen-containing hetero ring” refers to one containing at leastone nitrogen atom, as in (1)(a), (1)(b), (2)(a), (2)(b), (3)(a), (3)(b),(4)(a), (4)(b), and the like, among the “hetero rings” above.

The “aromatic hetero ring” refers to a ring group having an aromaticproperty, among (2) and (4) of the “hetero rings” above. Examplesthereof include pyrrolyl, furyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, quinolyl, isoquinolyl, and the like.

The “5-membered aromatic hetero ring” refers to a ring group having a5-membered ring structure, among the “aromatic hetero rings” above.Examples thereof include pyrrolyl, furyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the like.

The “aromatic nitrogen-containing hetero ring” refers to a ring grouphaving an aromatic property, among the nitrogen-containing hetero rings”above. Examples thereof include pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like.

The “nitrogen-containing monocyclic saturated hetero ring” refers tothose having at least one nitrogen atom, among the “monocyclic saturatedhetero rings” above as in (1)(a), (1)(b), and the like.

The “5-membered aromatic nitrogen-containing hetero ring” refers tothose having at least one nitrogen atom, among the “5-membered aromatichetero rings” above. Examples thereof include pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the like.

The expression “R^(X1) and R^(X2) are combined with each other to formC₂₋₅ alkylene” indicates that R^(X1) and R^(X2) are combined with carbonatoms to which they are bonded to form a C₃₋₆ saturated hydrocarbonring. Examples of the saturated hydrocarbon ring include cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like, in anotherembodiment, C₂₋₄ alkylene, and in a still another embodiment, C₂₋₃alkylene.

The expression “R³ and R⁴ are combined with each other to form C₂₋₅alkylene” indicates that R³ and R⁴ are combined with nitrogen atoms andsulfur atoms to which they are bonded to form a nitrogen-containinghetero ring having a —N—SO₂-moiety structure and having 2 to 5 carbonatoms. Examples of the nitrogen-containing hetero ring include1,1-dioxoisothiazolidinyl.

The expression “R¹⁰¹ and R¹⁰² may be combined with nitrogen atoms towhich they are bonded to form a nitrogen-containing monocyclic saturatedhetero ring” indicates that R¹⁰¹ and R¹⁰² are combined to form a ringcontaining nitrogen atom to which they are bonded, and represents a ringgroup such as a nitrogen-containing monocyclic saturated hetero ring.

The expression “R^(X1) may be combined with adjacent R^(X1) to form anew bond” indicates that R^(X1) is combined with adjacent R^(X1) to forma double bond, and represents, for example, —(CR^(X2))═(CR^(X2))—.

The “halogen” means F, Cl, Br, or I, and preferably F.

In the present specification, the “diseases caused by LPA” refers to,for example, diseases such as urinary system diseases (benign prostatichyperplasia (urinary disfunction associated with benign prostatichyperplasia, and the like), overactive bladder, neurogenic bladder,bladder neck sclerosis, underactive bladder, and the like),central/peripheral neuropathy (neurogenic pain, painful peripheraldiabetic neuropathy, nerve cell degeneration/nerve cell death afterstroke, and the like), cancer-related diseases (prostate cancer, breastcancer, ovarian cancer, lung cancer, colon cancer, and the like),inflammatory diseases (rheumatoid arthritis, knee osteoarthritis,hepatitis C, and non-alcoholic steatohepatitis), diseases associatedwith fibrosis (chronic renal diseases, idiopathic pulmonary fibrosis,and chronic rejection after non-organ transplantation), cardiovasculardiseases such as arteriosclerosis and the like. In another embodiment,examples of the diseases caused by LPA include urinary system diseases(benign prostatic hyperplasia (urinary disfunction associated withbenign prostatic hyperplasia, and the like), overactive bladder,neurogenic bladder, bladder neck sclerosis, underactive bladder, and thelike).

The expression “which may be substituted” represents non-substitution orsubstitution with 1 to 5 substituents”. Further, if it has a pluralityof substituents, the substituents may be the same as or different fromone other. For example, —N(lower alkyl)₂ refers to an ethylmethylaminogroup.

Examples of the substituent in “lower alkyl which may be substituted”and “lower alkenyl which may be substituted” in R¹⁰¹ and R¹⁰² includethe groups shown in (a) to (k) below.

(a) halogen.

(b) —OH, —O-lower alkyl (in which the lower alkyl may be substitutedwith 1 to 3 OH, halogen, —O-lower alkyl (in which the lower alkyl may besubstituted with one or more —COOH groups), or aryl groups).

(c) amino which may be substituted with one or two lower alkyl groups ornitro.

(d) —SH, —S-lower alkyl (in which the lower alkyl may be substitutedwith 1 to 3 halogen atoms).

(e) —SO₂-lower alkyl, —SO₂-cycloalkyl, —SO₂-hetero ring, —SO₂-aryl,sulfamoyl which may be substituted with one or two lower alkyl groups.

(f) —CHO, —CO-lower alkyl (in which the lower alkyl may be substitutedwith 1 to 3 halogen atoms), —CO-cycloalkyl (in which cycloalkyl may besubstituted with one or more —O-lower alkyl groups), —CO-monocyclicsaturated hetero ring, cyano.

(g) aryl or cycloalkyl; further, these groups may be substituted with 1to 5 halogen atoms or one or more —O-lower alkyl groups.

(h) a hetero ring, and in another embodiment, a monocyclic hetero ring;further, these hetero rings and monocyclic hetero rings may besubstituted with halogen or lower alkyl (in which the lower alkyl may besubstituted with one or more aryl groups).

(i) —COOH, —COO-lower alkyl (in which the lower alkyl may be substitutedwith 1 to 3 halogen atoms).

(j)—CONH₂, —CONH(lower alkyl) (in which the lower alkyl may besubstituted with 1 to 3 halogen atoms), —CONH(lower alkyl)₂ (in whichthe lower alkyl may be substituted with 1 to 3 halogen atoms).

(k) —O—CO-lower alkyl (in which the lower alkyl may be substituted with1 to 3 halogen atoms or aryl groups), —O—CO—O-lower alkyl (in which thelower alkyl may be substituted with 1 to 3 halogen atoms).

(l) lower alkyl which may be substituted with one or more groupsselected from the substituents shown in (a) to (k).

Examples of the substituents that can be used in the “aryl which may besubstituted” and the “aromatic hetero ring which may be substituted” inA include the groups shown in (a) to (l) above, lower alkenyl (in whichthe lower alkenyl may be substituted with 1 to 3 halogen atoms) andlower alkynyl (in which the lower alkynyl may be substituted with 1 to 3halogen atoms), and in another embodiment, the groups shown in (a), (b),(f), (k), and (l) above.

Examples of the substituents that can be used in the “5-memberedaromatic hetero ring” in B include the groups shown in (a) to (l) above,lower alkenyl (in which the lower alkenyl may be substituted with 1 to 3halogen atoms) and lower alkynyl (in which the lower alkynyl may besubstituted with 1 to 3 halogen atoms), and in another embodiment, thegroups shown in (a), (b), (f), (k), and (l) above.

Examples of the substituents that can be used in the “lower alkyl whichmay be substituted” and the “lower alkenyl which may be substituted” inR^(Y) include the groups shown in (a) to (k) above, and in anotherembodiment, the groups shown in (a) and (b) above.

Examples of the substituents that can be used in the “cycloalkyl whichmay be substituted” in R^(Y) include the groups shown in (a) to (l)above, and in another embodiment, the groups shown in (a) and (b) above.

Examples of the substituents that can be used in the “lower alkyl whichmay be substituted” in R^(X1) and R^(X2) and “R^(X1) and R^(X2) arecombined with each other to form C₂₋₅ alkylene which may be substituted”include the groups shown in (a) to (k) above, and in another embodiment,the groups shown in (a).

Examples of the substituents that can be used in the “R³ and R⁴ arecombined with each other to form C₂₋₅ alkylene which may be substituted”include the groups shown in (a) to (k) above, and in another embodiment,the groups shown in (a) above and oxo (═O).

Examples of the substituents that can be used in the “lower alkyl whichmay be substituted” and the “lower alkenyl which may be substituted” inR⁴ include the groups shown in (a) to (k) above, and in anotherembodiment, the groups shown in (a), (b), (g), and (j) above.

Examples of the substituents that can be used in the “aryl which may besubstituted” in R⁴ include the groups shown in (a) to (k) above, and inanother embodiment, the groups shown in (a), (b), (g), (k), and (l)above.

Examples of the substituents that can be used in the “cycloalkyl whichmay be substituted” and the “hetero ring which may be substituted” in R⁴include the groups shown in (a) to (l) above and oxo (═O), and inanother embodiment, the groups shown in (a), (b), (g), (k), and (I)above and oxo (═O).

Examples of the substituents that can be used in the “lower alkyl whichmay be substituted” in R¹ and R² include the groups shown in (a) to (k)above, and in another embodiment, the groups shown in (a) above.

Examples of the substituents that can be used in the “lower alkyl whichmay be substituted” in R³ include the groups shown in (a) to (k) above,and in another embodiment, the groups shown in (a) above.

Examples of the substituents that can be used in the “aryl which may besubstituted” in R¹⁰¹ and R¹⁰² include the groups shown in (a) to (l)above, and in another embodiment, the groups shown in (a), (b), and (l)above.

Examples of the substituents that can be used in the “cycloalkyl whichmay be substituted” and the “hetero ring which may be substituted” inR¹⁰¹ and R¹⁰² include the groups shown in (a) to (l) above and oxo (═O),and in another embodiment, the groups shown in (a), (b), and (l) above.

Embodiments of the compound (I) of the present invention include acompound of the formula (I′) or a salt thereof.

(wherein

A is aryl which may be substituted, or a hetero ring group which may besubstituted,

B is a 5-membered aromatic hetero ring group which may be substituted,

X is a single bond or —(CR^(X1)R^(X2))_(n)—,

n is 1, 2, 3, or 4,

R^(X1) and R^(X2) are the same as or different from each other, and areH, halogen, OH, —O-(lower alkyl which may be substituted), or loweralkyl which may be substituted, or

R^(X1) and R^(X2) are combined with each other to form oxo (═O), or

R^(X1) and R^(X2) are combined with each other to form C₂₋₅ alkylenewhich may be substituted,

in which n is 2, 3, or 4, R^(X1) may be combined with adjacent R^(X1) toform a new bond,

Y¹, Y², Y³, Y⁴ and Y⁵ are the same as or different from each other, andare CR^(Y) or N,

R^(Y)'s are the same as or different from each other, and are H, OH,halogen, —O-(lower alkyl which may be substituted), lower alkyl whichmay be substituted, lower alkenyl which may be substituted, orcycloalkyl which may be substituted,

R¹ and R² are the same as or different from each other, and are H,halogen, —O-(lower alkyl which may be substituted), or lower alkyl whichmay be substituted,

m is 1, 2, or 3,

R³ is H, or lower alkyl which may be substituted,

R⁴ is lower alkyl which may be substituted, lower alkenyl which may besubstituted, cycloalkyl which may be substituted, aryl which may besubstituted, a hetero ring group which may be substituted, or NR¹⁰¹R¹⁰²,or

R³ and R⁴ may be combined with each other to form C₂₋₅ alkylene whichmay be substituted, and

R¹⁰¹ and R¹⁰² are the same as or different from each other, and are H,OH, —O-(lower alkyl which may be substituted), —C(═O)-(lower alkyl whichmay be substituted), —C(═O)—O-(lower alkyl which may be substituted),—NH—C(═O)-(lower alkyl which may be substituted), lower alkyl which maybe substituted, lower alkenyl which may be substituted, cycloalkyl whichmay be substituted, aryl which may be substituted, or a hetero ringgroup which may be substituted, or

R¹⁰¹ and R¹⁰² may be combined with nitrogen atoms to which they arebonded to form a nitrogen-containing monocyclic saturated hetero ringgroup,

in which when R⁴ is NR¹⁰¹R¹⁰², at least one of R³, R¹⁰¹, and R¹⁰² is H.)

Embodiments of the compounds (I) and (I′) include the followingcompounds or salts thereof.

(1) The compound, wherein A is aryl which may be substituted withhalogen or an aromatic hetero ring which may be substituted withhalogen.

(2) The compound, wherein A is phenyl.

(3) The compound, wherein B is thiazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 4-position, pyrazole-1,3-diyl which is bonded with—C(═O)—NR³— at the 3-position, pyrazole-1,4-diyl which is bonded with—C(═O)—NR³— at the 4-position, oxazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiophene-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiophene-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, furan-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, furan-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, isoxazole-3,5-diyl which is bonded with—C(═O)—NR³— at the 5-position, or pyrrole-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, each of which may be substituted.

(4) The compound, wherein B is thiazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 4-position, pyrazole-1,3-diyl which is bonded with—C(═O)—NR³— at the 3-position, oxazole-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiophene-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, thiophene-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, 5-methoxymethylthiophene-2,4-diyl whichis bonded with —C(═O)—NR³— at the 2-position, 5-chlorothiophene-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, furan-2,5-diyl whichis bonded with —C(═O)—NR³— at the 2-position, 5-chlorothiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, or5-methylthiazole-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position

(5) The compound, wherein X is a single bond.

(6) The compound, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) andR^(X2) are the same as or different from each other, and are H, OH,—O-(lower alkyl which may be substituted), or R^(X1) and R^(X2) arecombined with each other to form oxo (═O), or C₂₋₅ alkylene which may besubstituted.

(7) The compound, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) isH, and R^(X2) is OH or methoxy.

(8) The compound, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) andR^(X2) are combined with each other to form oxo (═O), trimethylene, orethylene.

(9) The compound, wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s arethe same as or different from each other, and are H, OH, halogen,—O-(lower alkyl which may be substituted with halogen or —O-loweralkyl), lower alkyl which may be substituted with halogen or —O-loweralkyl, or cycloalkyl which may be substituted with halogen or —O-loweralkyl.

(10) The compound, wherein Y² and Y⁴ is CR^(Y11), R^(Y11)'s are the sameas or different from each other, and are H, F, methyl, or methoxy, Y¹,Y³, and Y⁵ are CR^(Y21), R^(Y21)'s are the same as or different fromeach other, and are H, OH, bromo, methyl, difluoromethyl, ethyl,ethenyl, isopropenyl, methoxy, methoxymethyl, 2-fluoroethoxy, orcyclopropyl.

(11) The compound, wherein Y² and Y⁴ is C—CH₃, Y³ is C—O—CH₃, Y¹ and Y⁵are CH.

(12) The compound, wherein m is 3, R¹ and R² are the same as ordifferent from each other, and are H, halogen, —O-(lower alkyl which maybe substituted with halogen), or lower alkyl which may be substitutedwith halogen.

(13) The compound, wherein m is 3, R¹ and R² are the same as ordifferent from each other, and are H, F, methyl, or methoxy.

(14) The compound, wherein R³ is H, R⁴ is lower alkyl which may besubstituted with —OH, —O—C(═O)-lower alkyl, —O—C(═O)—O-lower alkyl,O-lower alkyl, or aryl; lower alkenyl which may be substituted withhalogen; aryl which may be substituted with halogen or lower alkyl;hetero ring which may be substituted with halogen or lower alkyl; orcycloalkyl which may be substituted with halogen or lower alkyl, or R³and R⁴ may be combined with each other to form C₂₋₅ alkylene which maybe substituted with halogen or oxo (═O).

(15) The compound, wherein R³ is H, R⁴ is lower alkyl which may besubstituted with —OH, —O—C(═O)-lower alkyl, —O—C(═O)—O-lower alkyl,O-lower alkyl, or aryl; vinyl which may be substituted with halogen;aryl which may be substituted with halogen or methyl; pyridine which maybe substituted with halogen or methyl; thiophene; thiazole; imidazole;oxazole; or cycloalkyl which may be substituted with halogen or methyl,or R³ and R⁴ may be combined with each other to form ethylene which maybe substituted with halogen.

(16) The compound, wherein R³ is H, R⁴ is vinyl, methyl,trifluoromethyl, benzyl, 2-hydroxy-2-methyl-ethyl, ethyl,2-(acetoxy)ethyl, 2-methoxyethyl, 2-(ethoxycarbonyloxy)ethyl,2-hydroxy-2,2-dimethyl-ethyl, isopropyl, 4-(acetoxy)butyl,4-hydroxybutyl, phenyl, 5-methylpyridin-2-yl, 4-chloropyridin-3-yl,thiophen-3-yl, 2-methylthiazol-4-yl, 2-methylimidazol-4-yl,3,5-dimethyloxazol-4-yl, or cyclopropyl, or R³ and R⁴ may be combinedwith each other to form ethylene.

(17) The compound, wherein R³ is H, R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹, and R¹⁰² arethe same as or different from each other, and are H, —O-(lower alkylwhich may be substituted with halogen), —C(═O)-(lower alkyl which may besubstituted with halogen), —C(═O)—O-(lower alkyl which may besubstituted with halogen), lower alkyl which may be substituted withhalogen or OH, or hetero ring which may be substituted with halogen orOH, or R¹⁰¹ and R¹⁰² are combined with nitrogen atoms to which they arebonded to form a nitrogen-containing monocyclic saturated hetero ringwhich may be substituted with halogen or oxo (═O).

(18) The compound, wherein R³ is H, R⁴ is NR¹⁰², R¹⁰¹ is H, and R¹⁰² isH, methoxy, acetyl, methoxycarbonyl, methyl, ethyl, 2-fluoroethyl,2-hydroxyethyl, or pyridin-2-yl.

Other embodiments of the compounds (I) and (I′) include the followingcompounds or salts thereof.

(19) The compound, wherein A is phenyl which may be substituted withhalogen, or a 5-membered aromatic hetero ring which may be substitutedwith halogen or lower alkyl.

(20) The compound, wherein A is 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3-methylphenyl, 3-difluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 3-methylphenyl, 3-ethylphenyl,3-butylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3-methylphenyl,3-bromophenyl, 3-chlorophenyl, or phenyl.

(21) The compound, wherein A is furyl which may be substituted withhalogen or lower alkyl, or thiophenyl which may be substituted withhalogen or lower alkyl.

(22) The compound, wherein A is furan-2-yl, 5-methylfuran-2-yl,4,5-dimethylfuran-2-yl, 5-chlorofuran-2-yl, 5-ethylthiophen-2-yl,thiophen-2-yl, 2-methylthiophen-2-yl, 3-methylthiophen-2-yl,4-methylthiophen-2-yl, 4,5-dimethylthiophen-2-yl, or5-chlorothiophen-2-yl.

(23) The compound, wherein B is a 5-membered aromaticnitrogen-containing hetero ring.

(24) The compound, wherein B is

L is O or S,

R^(L1) is H, halogen, lower alkyl which may be substituted, loweralkenyl which may be substituted, lower alkynyl which may besubstituted, or cycloalkyl which may be substituted,

R^(L2) is H, halogen, lower alkyl which may be substituted, loweralkenyl which may be substituted, lower alkynyl which may besubstituted, or cycloalkyl which may be substituted.

(25) The compound as described in (24), wherein B is the formula (III).

(26) The compound as described in (24), wherein R^(L1) are H, halogen,or lower alkyl which may be substituted with halogen or OH.

(27) The compound as described in (24), wherein R^(L1) is H.

(28) The compound as described in (24), wherein B is the formula (II)and L is O.

(29) The compound as described in (24), wherein B is the formula (II)and L is S.

(30) The compound as described in (24), wherein R^(L2) are H, halogen,or lower alkyl which may be substituted with halogen or OH.

(31) The compound as described in (24), wherein R^(L2) are H, Cl, ormethyl.

(32) The compound, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) isH, and R^(X2) is OH.

(33) The compound, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, andR^(X1) and R^(X2) are combined with each other to form ethylene.

(34) The compound, wherein R^(Y)'s are the same as or different fromeach other, and are H, OH, halogen, —O-(lower alkyl which may besubstituted with halogen or —O-lower alkyl), lower alkyl which may besubstituted with halogen or —O-lower alkyl, or cycloalkyl which may besubstituted with halogen or —O-lower alkyl.

(35) The compound, wherein R^(Y)'s are the same as or different fromeach other, and are H, OH, halogen, lower alkyl, or —O-(lower alkyl).

(36) The compound, wherein R^(Y)'s are the same as or different fromeach other, and are H, OH, halogen, methyl, or methoxy.

(37) The compound, wherein Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s arethe same as or different from each other, and are H, OH, halogen,—O-(lower alkyl which may be substituted with halogen or —O-loweralkyl), lower alkyl which may be substituted with halogen or —O-loweralkyl, or cycloalkyl which may be substituted with halogen or —O-loweralkyl, and Y¹ is N.

(38) The compound, wherein Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s arethe same as or different from each other, and are H, or —O-(loweralkyl), and Y¹ is N.

(39) The compound, wherein Y², Y⁴, and Y⁵ are CH, and Y³ is C—O—CH₃, andY¹ is N.

(40) The compound, wherein Y¹, Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s arethe same as or different from each other, and are H, OH, halogen,—O-(lower alkyl which may be substituted with halogen or —O-loweralkyl), lower alkyl which may be substituted with halogen or —O-loweralkyl, or cycloalkyl which may be substituted with halogen or —O-loweralkyl, and Y² is N.

(41) The compound, wherein Y¹, Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s arethe same as or different from each other, and are H, or —O-(loweralkyl), and Y² is N.

(42) The compound, wherein Y¹, Y⁴, and Y⁵ are CH, Y³ is C—O—CH₃, and Y²is N.

(43) The compound, wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'sare the same as or different from each other, and are H, OH, halogen,—O-(lower alkyl which may be substituted with halogen or —O-loweralkyl), lower alkyl which may be substituted with halogen or —O-loweralkyl, or cycloalkyl which may be substituted with halogen or —O-loweralkyl.

(44) The compound, wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), andR^(Y)'s are the same as or different from each other, and are H, loweralkyl, or —O-(lower alkyl).

(45) The compound, wherein Y¹, Y², Y⁴, and Y⁵ are CH, Y³ is C—O—CH₃.

(46) The compound, wherein Y² and Y⁴ are C—O—CH₃, Y³ is C—CH₃, and Y¹and Y⁵ are CH.

(47) The compound, wherein R³ is H.

(48) The compound, wherein R³ is methyl.

(49) The compound, wherein R⁴ is lower alkyl which may be substituted,cycloalkyl which may be substituted, aryl which may be substituted, or anitrogen-containing hetero ring group which may be substituted, orNR¹⁰¹R¹⁰².

(50) The compound, wherein R⁴ is lower alkyl (in which the lower alkylmay be substituted with halogen, OH, or —O—C(O)-lower alkyl), cycloalkylwhich may be substituted with a group selected from Group G¹, aryl whichmay be substituted with a group selected from Group G¹, a 5-memberednitrogen-containing hetero ring group which may be substituted with agroup selected from Group G¹, or NR¹⁰¹R¹⁰², in which Group G¹ ishalogen, OH, lower alkyl, or —O—C(O)-lower alkyl, R¹⁰¹ and R¹⁰² are thesame as or different from each other, and are H, OH, —C(═O)-halogen,—O-(lower alkyl which may be substituted), —C(═O)-(lower alkyl which maybe substituted), —C(═O)—O-(lower alkyl which may be substituted),—NH—C(═O)-(lower alkyl which may be substituted), lower alkyl which maybe substituted, lower alkenyl which may be substituted, cycloalkyl whichmay be substituted, aryl which may be substituted, or a hetero ringgroup which may be substituted.

(51) The compound, wherein R⁴ is lower alkyl (in which the lower alkylmay be substituted with halogen, OH, or —O—C(O)-lower alkyl), a5-membered nitrogen-containing hetero ring group which may besubstituted with lower alkyl, cycloalkyl, aryl, or NR¹⁰¹R¹⁰², R¹⁰¹ andR¹⁰² are the same as or different from each other, and are H, halogen,OH, COOH, —COO-lower alkyl, C(═O)—NH₂, O-(lower alkyl which may besubstituted with halogen), lower alkyl (in which the lower alkyl may besubstituted with halogen, OH, S-lower alkyl, or a hetero ring group),—C(═O)—O-(lower alkyl which may be substituted with aryl), a hetero ringgroup which may be substituted with lower alkyl, or lower alkenyl.

(52) The compound, wherein R⁴ is ethyl which may be substituted with agroup selected from Group G¹, methyl which may be substituted withhalogen, propyl which may be substituted with OH, oxazole which may besubstituted with lower alkyl, imidazole which may be substituted withlower alkyl, isopropyl, cyclopropyl, phenyl, or NR¹⁰¹R¹⁰², in whichGroup G¹ is halogen, OH, or —O—C(O)-lower alkyl, and R¹⁰¹ and R¹⁰² arethe same as or different from each other, and are lower alkyl (in whichthe lower alkyl may be substituted with H, halogen, OH, S-lower alkyl,or a hetero ring group.

(53) The compound, wherein R⁴ is methyl, trifluoromethyl, halogen,2-hydroxyethyl, 2-acetoxyethyl, propyl, 2-hydroxypropyl,3-hydroxypropyl, isopropyl, cyclopropyl, phenyl,3,5-dimethylisoxazol-4-yl, 1-methyl-1H-imidazol-4-yl, or NR¹⁰¹R¹⁰²,R¹⁰¹, and R¹⁰² are the same as or different from each other, and are H,methyl which may be substituted with, halogen, or OH, ethyl which may besubstituted with halogen or OH, or propyl which may be substituted withhalogen or OH.

(54) The compound, wherein R⁴ is lower alkyl (in which the lower alkylmay be substituted with halogen, OH, or —O—C(O)-lower alkyl), orcycloalkyl which may be substituted with a group selected from Group G¹,aryl which may be substituted with a group selected from Group G¹, or a5-membered nitrogen-containing hetero ring group which may besubstituted with a group selected from Group G¹, in which Group G¹ ishalogen, OH, lower alkyl, or —O—C(O)-lower alkyl.

(55) The compound, wherein R⁴ is lower alkyl (in which the lower alkylmay be substituted with halogen, OH, or —O—C(O)-lower alkyl), a5-membered nitrogen-containing hetero ring group which may besubstituted with lower alkyl, cycloalkyl, or aryl.

(56) The compound, wherein R⁴ is methyl which may be substituted withhalogen, ethyl (in which ethyl may be substituted with halogen, OH, or—O—C(O)-lower alkyl), propyl which may be substituted with OH, oxazolewhich may be substituted with lower alkyl, imidazole which may besubstituted with lower alkyl, isopropyl, cyclopropyl, or phenyl.

(57) The compound, wherein R⁴ is methyl, trifluoromethyl, halogen,2-hydroxyethyl, 2-acetoxyethyl, propyl, 2-hydroxypropyl,3-hydroxypropyl, isopropyl, cyclopropyl, phenyl,3,5-dimethylisoxazol-4-yl, or 1-methyl-1H-imidazol-4-yl.

(58) The compound, wherein R⁴ is methyl, trifluoromethyl, halogen,2-hydroxyethyl, 2-acetoxyethyl, propyl, 2-hydroxypropyl,3-hydroxypropyl, or isopropyl.

(59) The compound, wherein R⁴ is cyclopropyl, phenyl,3,5-dimethylisoxazol-4-yl, 2,4-dimethylthiazol-5-yl, or1-methyl-1H-imidazol-4-yl.

(60) The compound, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² is H,O-(lower alkyl which may be substituted), lower alkyl which may besubstituted, —C(═O)—O-(lower alkyl which may be substituted), a heteroring group which may be substituted, or lower alkenyl which may besubstituted.

(61) The compound, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² is H,O-(lower alkyl which may be substituted with halogen), lower alkyl (inwhich the lower alkyl may be substituted with halogen, OH, S-loweralkyl, or a hetero ring group), —C(═O)—O-(lower alkyl which may besubstituted with aryl), a hetero ring group which may be substitutedwith lower alkyl, or lower alkenyl.

(62) The compound, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² is loweralkyl (in which the lower alkyl may be substituted with halogen, OH,S-lower alkyl, or a hetero ring group).

(63) The compound, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² ismethyl which may be substituted with a group selected from Group G²,ethyl which may be substituted with a group selected from Group G², orpropyl which may be substituted with a group selected from Group G², inwhich Group G² is halogen, OH, S-lower alkyl, or a hetero ring group.

(64) The compound, wherein R⁴ is NR¹⁰¹, R¹⁰², R¹⁰¹ is H, and R¹⁰² ismethyl, ethyl, or propyl.

(65) The compound, wherein R⁴ is NR¹⁰¹R¹⁰², and R¹⁰¹ and R¹⁰² are thesame as or different from each other, and are O-(lower alkyl which maybe substituted with halogen), lower alkyl (in which the lower alkyl maybe substituted with halogen, OH, S-lower alkyl, or a hetero ring group),—C(═O)—O-(lower alkyl which may be substituted with aryl), a hetero ringgroup which may be substituted with lower alkyl, or lower alkenyl.

(66) The compound, wherein R⁴ and NR¹⁰¹R¹⁰², and R¹⁰¹ and R¹⁰² are thesame as or different from each other, and are lower alkyl (in which thelower alkyl may be substituted with halogen, OH, S-lower alkyl, or ahetero ring group).

(67) The compound, wherein R⁴ and NR¹⁰¹R¹⁰², and R¹⁰¹ and R¹⁰² are thesame as or different from each other, and are lower alkyl which may besubstituted with halogen or OH.

(68) R⁴ and NR¹⁰¹R¹⁰², and R¹⁰¹ and R¹⁰² are the same as or differentfrom each other, and are methyl which may be substituted with halogen orOH, ethyl which may be substituted with halogen or OH, or propyl whichmay be substituted with halogen or OH.

Furthermore, still other embodiments of the compounds (I) and (I′) ofthe present invention include the compounds or salts thereof includingthe combinations of two or more of the groups as described in (1) to(18), and specifically the following compounds or salts thereof.

(69) The compound as described in (14) to (18), wherein A is aryl whichmay be substituted with halogen, or an aromatic hetero ring which may besubstituted with halogen, B is a monocyclic aromatic hetero ring whichmay be substituted, Y¹, Y², Y³, Y⁴ and Y⁵ are CR^(Y), R^(Y)'s are thesame as or different from each other, and are H, OH, halogen, —O-(loweralkyl which may be substituted with halogen or —O-lower alkyl), loweralkyl which may be substituted with halogen or —O-lower alkyl, orcycloalkyl which may be substituted with halogen or —O-lower alkyl, m is3, and R¹ and R² are the same as or different from each other, and areH, halogen, —O-(lower alkyl which may be substituted with halogen), orlower alkyl which may be substituted with halogen.

(70) The compound as described in (69), wherein B is thiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 4-position, pyrazole-1,3-diylwhich is bonded with —C(═O)—NR³— at the 3-position, pyrazole-1,4-diylwhich is bonded with —C(═O)—NR³— at the 4-position, oxazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiophene-2,5-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiophene-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, furan-2,5-diyl whichis bonded with —C(═O)—NR³— at the 2-position, furan-2,4-diyl which isbonded with —C(═O)—NR³— at the 2-position, isoxazole-3,5-diyl which isbonded with —C(═O)—NR³— at the 5-position, or pyrrole-2,5-diyl which isbonded with —C(═O)—NR³— at the 2-position, each of which may besubstituted.

(71) The compound as described in (69), wherein B is thiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 4-position, pyrazole-1,3-diylwhich is bonded with —C(═O)—NR³— at the 3-position, oxazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiophene-2,5-diylwhich is bonded with —C(═O)—NR³— at the 2-position, thiophene-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position,5-methoxymethylthiophene-2,4-diyl which is bonded with —C(═O)—NR³— atthe 2-position, 5-chlorothiophene-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, furan-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, 5-chlorothiazole-2,4-diyl which is bondedwith —C(═O)—NR³— at the 2-position, or 5-methylthiazole-2,4-diyl whichis bonded with —C(═O)—NR³— at the 2-position.

(72) The compound as described in (69), (70), or (71), wherein A isphenyl.

(73) The compound as described in (69) to (72), wherein Y² and Y⁴ areCR^(Y11), R^(Y11)'s are the same as or different from each other, andare H, F, methyl, or methoxy, Y′, Y³, and Y⁵ are CR^(Y21), and R^(Y21)'sare the same as or different from each other, and are H, OH, bromo,methyl, difluoromethyl, ethyl, ethenyl, isopropenyl, methoxy,methoxymethyl, 2-fluoroethoxy, or cyclopropyl.

(74) The compound as described in (69) to (72), wherein Y² and Y⁴ areC—CH₃, Y³ is C—O—CH₃, and Y¹ and Y⁵ are CH.

(75) The compound as described in (69) to (74), wherein X is a singlebond.

(76) The compound as described in (69) to (74), wherein X is—(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) and R^(X2) are the same as ordifferent from each other, and are H, OH, —O-(lower alkyl which may besubstituted), or R^(X1) and R^(X2) are combined with each other to formoxo (═O) or C₂₋₅ alkylene which may be substituted.

(77) The compound as described in (69) to (74), wherein X is—(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) is H, R^(X2) is OH or methoxy.

(78) The compound as described in (69) to (74), wherein X is—(CR^(X1)R^(X2))n-, n is 1, and R^(X1) and R^(X2) are combined with eachother to form oxo (═O), trimethylene or ethylene.

(79) The compound as described in (69) to (78), wherein m is 3, R¹ andR² are the same as or different from each other, and are H, F, methyl,or methoxy.

(80) The compound as described in (69) to (79), wherein L is a singlebond.

(81) The compound as described in (69) to (79), wherein L is—(CR^(L1)R^(L2))_(p)—, J-(O)_(q)—(CR^(L3)R^(L4))_(r)—, p is 1, J is asingle bond, q is 0, r is 0, and R^(L1) and R^(L2) are both H.

(82) The compound as described in (69) to (79), wherein L is—(CR^(L1)R^(L2))_(p)-J-(O)_(q)—(CR^(L3)R^(L4))_(r)—, p is 1, J is asingle bond, q is 0, r is 0, R^(L1) is H, and R^(L2) is 2-methoxyethyl,methoxy, cyclopropyl, or —C(═O)—O—CH₃.

(83) The compound as described in (69) to (82), wherein B isthiazole-2,4-diyl which is bonded with —C(═O)—NR³— at the 2-position, or5-methylthiazole-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position.

(84) The compound as described in (69) to (82), wherein B ispyrazole-1,3-diyl which is bonded with —C(═O)—NR³— at the 3-position,pyridine-2,6-diyl which is bonded with —C(═O)—NR³— at the 2-position,oxazole-2,4-diyl which is bonded with —C(═O)—NR³— at the 2-position,thiophene-2,5-diyl which is bonded with —C(═O)—NR³— at the 2-position,thiophene-2,4-diyl which is bonded with —C(═O)—NR³— at the 2-position,5-methoxymethylthiophene-2,4-diyl which is bonded with —C(═O)—NR³— atthe 2-position, 5-chlorothiophene-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, furan-2,5-diyl which is bonded with—C(═O)—NR³— at the 2-position, or pyrazine-2,6-diyl which is bonded with—C(═O)—NR³— at the 2-position.

In addition, further still other embodiments of the compounds (I) and(I′) of the present invention include the compounds or salts thereofincluding the combinations of two or more of the groups as described in(1) to (68), and specifically the following compounds or salts thereof.

(85) The compound as described in (14) to (18), or (49) to (68), whereinA is aryl which may be substituted with halogen, or an aromatic heteroring which may be substituted with halogen.

(86) The compound as described in (14) to (18), or (49) to (68), whereinA is phenyl.

(87) The compound as described in (14) to (18), or (49) to (68), whereinA is phenyl which may be substituted with halogen, or a 5-memberedaromatic hetero ring which may be substituted with halogen or loweralkyl.

(88) The compound as described in (14) to (18), or (49) to (68), whereinA is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl,3-difluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl,3-methylphenyl, 3-ethylphenyl, 3-butylphenyl, 2-fluoro-5-methylphenyl,2-fluoro-3-methylphenyl, 3-bromophenyl, 3-chlorophenyl, or phenyl.

(89) The compound as described in (14) to (18), or (49) to (68), whereinA is furyl which may be substituted with halogen or lower alkyl, orthiophenyl which may be substituted with halogen or lower alkyl.

(90) The compound as described in (14) to (18), or (49) to (68), whereinA is furan-2-yl, 5-methylfuran-2-yl, 4,5-dimethylfuran-2-yl,5-chlorofuran-2-yl, 5-ethylthiophen-2-yl, thiophen-2-yl,2-methylthiophen-2-yl, 3-methylthiophen-2-yl, 4-methylthiophen-2-yl,4,5-dimethylthiophen-2-yl, or 5-chlorothiophen-2-yl.

(91) The compound as described in (14) to (18), (49) to (68), or (85) to(90), wherein B is thiazole-2,4-diyl which is bonded with —C(═O)—NR³— atthe 2-position, thiazole-2,4-diyl which is bonded with —C(═O)—NR³— atthe 4-position, pyrazole-1,3-diyl which is bonded with —C(═O)—NR³— atthe 3-position, pyrazole-1,4-diyl which is bonded with —C(═O)—NR³— atthe 4-position, oxazole-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position, thiophene-2,5-diyl which is bonded with —C(═O)—NR³— at the2-position, thiophene-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position, furan-2,5-diyl which is bonded with —C(═O)—NR³— at the2-position, furan-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position, isoxazole-3,5-diyl which is bonded with —C(═O)—NR³— at the5-position, or pyrrole-2,5-diyl which is bonded with —C(═O)—NR³— at the2-position, each of which may be substituted.

(92) The compound as described in (14) to (18), (49) to (68), or (85) to(90), wherein B is thiazole-2,4-diyl which is bonded with —C(═O)—NR³— atthe 2-position, thiazole-2,4-diyl which is bonded with —C(═O)—NR³— atthe 4-position, pyrazole-1,3-diyl which is bonded with —C(═O)—NR³— atthe 3-position, oxazole-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position, thiophene-2,5-diyl which is bonded with —C(═O)—NR³— at the2-position, thiophene-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position, 5-methoxymethylthiophene-2,4-diyl which is bonded with—C(═O)—NR³— at the 2-position, 5-chlorothiophene-2,4-diyl which isbonded with —C(═O)—NR³— at the 2-position, furan-2,5-diyl which isbonded with —C(═O)—NR³— at the 2-position, 5-chlorothiazole-2,4-diylwhich is bonded with —C(═O)—NR³— at the 2-position, or5-methylthiazole-2,4-diyl which is bonded with —C(═O)—NR³— at the2-position.

(93) The compound as described in (14) to (18), (49) to (68), or (85) to(90), wherein B is a 5-membered aromatic nitrogen-containing heteroring.

(94) The compound as described in (14) to (18), (49) to (68), or (85) to(90), wherein B is

L is O, or S,

R^(L1) are H, halogen, lower alkyl which may be substituted, loweralkenyl which may be substituted, lower alkynyl which may besubstituted, or cycloalkyl which may be substituted,

R^(L2) are H, halogen, lower alkyl which may be substituted, loweralkenyl which may be substituted, lower alkynyl which may besubstituted, or cycloalkyl which may be substituted.

(95) The compound as described in (94), wherein B is the formula (III).

(96) The compound as described in (94) or (95), wherein R^(L1) is H,halogen, or lower alkyl which may be substituted with halogen or OH.

(97) The compound as described in (94) or (95), wherein R^(L1) is H.

(98) The compound as described in (94), wherein B is the formula (II)and L is O.

(99) The compound as described in (94), wherein B is the formula (II)and L is S.

(100) The compound as described in (94) to (99), wherein R^(L2) are H,halogen, or lower alkyl which may be substituted with halogen or OH.

(101) The compound as described in (94) to (99), wherein R^(L2) is H,Cl, or methyl.

(102) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is a single bond.

(103) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is n is —(CR^(X1)R^(X2))_(n)—, R^(X1) and R^(X2) arethe same as or different from each other, and are H, OH, —O-(lower alkylwhich may be substituted), or R^(X1) and R^(X2) are combined with eachother to form oxo (═O) or C₂₋₅ alkylene which may be substituted.

(104) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) is H, andR^(X2) is OH or methoxy.

(105) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, and R^(X1) andR^(X2) are combined with each other to form oxo (═O), trimethylene orethylene.

(106) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1) is H, andR^(X2) is OH.

(107) The compound as described in (14) to (18), (49) to (68), or (85)to (101), wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, and R^(X1) andR^(X2) are combined with each other to form ethylene.

(108) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein R^(Y)'s are the same as or different from each other,and are H, OH, halogen, —O-(lower alkyl which may be substituted withhalogen or —O-lower alkyl), lower alkyl which may be substituted withhalogen or —O-lower alkyl, or cycloalkyl which may be substituted withhalogen or —O-lower alkyl.

(109) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein R^(Y)'s are the same as or different from each other,and are H, OH, halogen, lower alkyl, or —O-(lower alkyl).

(110) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein R^(Y)'s are the same as or different from each other,and are H, OH, halogen, methyl, or methoxy.

(111) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), and R^(Y)'s are thesame as or different from each other, and are H, OH, halogen, —O-(loweralkyl which may be substituted with halogen or —O-lower alkyl), loweralkyl which may be substituted with halogen or —O-lower alkyl, orcycloalkyl which may be substituted with halogen or —O-lower alkyl.

(112) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y² and Y⁴ are CR^(Y11), R^(Y11)'s are the same as ordifferent from each other, and are H, F, methyl, or methoxy, Y¹, Y³, andY⁵ are CR^(Y21), and R^(Y21)'s are H, OH, bromo, methyl, difluoromethyl,ethyl, ethenyl, isopropenyl, methoxy, methoxymethyl, 2-fluoroethoxy, orcyclopropyl.

(113) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y² and Y⁴ are C—CH₃, Y³ is C—O—CH₃, and Y¹ and Y⁵ areCH.

(114) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s are the same asor different from each other, and are H, OH, halogen, —O-(lower alkylwhich may be substituted with halogen or —O-lower alkyl), lower alkylwhich may be substituted with halogen or —O-lower alkyl, or cycloalkylwhich may be substituted with halogen or —O-lower alkyl, and Y¹ is N.

(115) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s are the same asor different from each other, and are H, or —O-(lower alkyl), and Y¹ isN.

(116) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y², Y⁴, and Y⁵ are CH, Y³ is C—O—CH₃, and Y¹ is N.

(117) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s are the same asor different from each other, and are H, OH, halogen, —O-(lower alkylwhich may be substituted with halogen or —O-lower alkyl), lower alkylwhich may be substituted with halogen or —O-lower alkyl, or cycloalkylwhich may be substituted with halogen or —O-lower alkyl, and Y² is N.

(118) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s are the same asor different from each other, and are H, or —O-(lower alkyl), and Y² isN.

(119) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y⁴, and Y⁵ are CH, Y³ is C—O—CH₃, and Y² is N.

(120) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), and R^(Y)'s are thesame as or different from each other, and are H, OH, halogen, —O-(loweralkyl which may be substituted with halogen or —O-lower alkyl), loweralkyl which may be substituted with halogen or —O-lower alkyl, orcycloalkyl which may be substituted with halogen or —O-lower alkyl.

(121) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), and R^(Y)'s are thesame as or different from each other, and are H, lower alkyl, or—O-(lower alkyl).

(122) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y¹, Y², Y⁴, and Y⁵ are CH, and Y³ is C—O—CH₃.

(123) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein Y² and Y⁴ are C—O—CH₃, Y³ is C—CH₃, and Y¹ and Y⁵ areCH.

(124) The compound as described in (14) to (18), (49) to (68), or (85)to (107), wherein m is 3, and R¹ and R² are the same as or differentfrom each other, and are H, halogen, —O-(lower alkyl which may besubstituted with halogen), or lower alkyl which may be substituted withhalogen.

(125) The compound as described in (14) to (18), (49) to (68), or (85)to (123), wherein m is 3, and R¹ and R² are the same as or differentfrom each other, and are H, F, methyl, or methoxy.

(126) The compound as described in (14) to (18), (49) to (68), or (85)to (125), wherein R³ is H.

(127) The compound as described in (14) to (18), (49) to (68), or (85)to (125), wherein R³ is methyl.

Specific examples of the compound included in the present inventioninclude the following compounds or salts thereof:

-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(2-thienylsulfonyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   5-chloro-2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-5-chloro-2-{[(4-hydroxy-3,5-dimethylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-oxazol-4-carboxamide,-   N-(aminosulfonyl)-2-{[(4-cyclopropyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-{[(4-bromo-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   N-(acetamidesulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(ethylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-({[3-(5-chloro-2-thienyl)propyl](3,5-dimethoxy-4-methylbenzoyl)amino}methyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(5-methyl-2-furyl)propyl]amino}methyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(2-fluorophenyl)propyl]amino}methyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-({[3-(2,5-difluorophenyl)propyl](3,5-dimethoxy-4-methylbenzoyl)amino}methyl)-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-4-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-2-carboxamide,-   2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   2-{[(4-ethyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(3-thienyl)propyl]amino}methyl)-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-methyl-1,3-thiazole-4-carboxamide,-   2-{[(4-cyclopropyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   methyl    ({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)methylcarbamate,-   N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-methyl-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-fluoroethyl)(methyl)amino]sulfonyl}-5-methyl-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(pyridin-2-yl    amino)sulfonyl]-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[ethyl(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-[(methoxyamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-fluoroethyl)(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   2-({[(2,4-dimethoxyphenyl)acetyl]    (3-phenylpropyl)amino}methyl)-N-[(dimethylamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,-   2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(2-hydroxypropyl)sulfonyl]-1,3-thiazole-4-carboxamide,-   2-({[3,5-dimethoxy-4-(methoxymethyl)benzoyl](3-phenylpropyl)amino}methyl)-N-[(methoxyamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,-   2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(2-fluorophenyl)propyl]amino}methyl)-N-[(dimethylamino)sulfonyl]-1,3-thiazole-4-carboxamide,-   2-({[hydroxy(4-methoxyphenyl)acetyl]    (3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   N-aminosulfonyl)-2-({[hydroxy(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   N-[(dimethylamino)sulfonyl]-2-({[(2-fluoro-4-methoxyphenyl)(hydroxy)acetyl](3-phenylpropyl)amino}methyl)-5-methyl    1-1,3-thiazole-4-carboxamide,-   N-[(dimethylamino)sulfonyl]-2-({[hydroxy(6-methoxypyridin-3-yl)acetyl    1](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-{[{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxamide,-   5-chloro-N-(dimethylsulfamoyl)-2-{[{[1-(6-methoxypyridin-3-yl)cyclopropyl]carbonyl}(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[({[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}[3-(5-methyl-2-furyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl]    (3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-{[(3-fluoro-3-phenylpropyl)    {[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino]methyl}-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[([3-(3-fluorophenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[({[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}[3-(2-thienyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[([3-(2-furyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-({[hydroxy(4-methoxy-2-methylphenyl)acetyl]    (3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   2-({[3-(3-fluorophenyl)propyl][(R2)-2-hydroxy-2-(4-methoxyphenyl)acetyl]amino}methyl)-5-methyl-N-sulfamoyl-1,3-thiazole-4-carboxamide,-   2-({]R2)-2-hydroxy-2-(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfamoyl)-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl][3-(2-thienyl)propyl]amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   5-bromo-N-(dimethylsulfamoyl)-2-({[(R2)-2-hydroxy-2-(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-1,3-thiazole-4-carboxamide,-   N-(ethylsulfonyl)-2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[([3-(2-furyl)propyl]{[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   N-(dimethylsulfamoyl)-2-[([3-(3-ethynylphenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide,-   2-({[3-(3-fluorophenyl)propyl][(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl]amino}methyl)-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   N-(ethylsulfonyl)-2-({[3-(3-fluorophenyl)propyl][(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl]amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   N-(ethylsulfonyl)-2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl][3-(2-thienyl)propyl]amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,-   2-({[(2R)-2-(2-fluoro-4-methoxyphenyl)-2-hydroxyacetyl](3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,-   2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl][3-(2-thienyl)propyl]amino}methyl)-5-methyl-N-(methylsulfamoyl)-1,3-thiazole-4-carboxamide,-   2-({[(2R)-2-(2-fluoro-4-methoxyphenyl)-2-hydroxyacetyl](3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfamoyl)-1,3-thiazole-4-carboxami,    or-   2-({[(2R)-2-hydroxy-2-(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-N-(isopropylsulfonyl)-5-methyl-1,3-thiazole-4-carboxamide.

The compound of the formula (I) may exist in the form of tautomers orgeometrical isomers depending on the kind of substituents. In thepresent specification, the compound of the formula (I) shall bedescribed in only one form of isomer, yet the present invention includesother isomers, isolated forms of the isomers, or a mixture thereof.

In addition, the compound of the formula (I) may have asymmetric carbonatoms or axial asymmetry in some cases, and correspondingly, it mayexist in the form of optical isomers based thereon. The presentinvention includes both an isolated form of the optical isomers of thecompound of the formula (I) or a mixture thereof.

Moreover, the present invention also includes a pharmaceuticallyacceptable prodrug of the compound represented by the formula (I). Thepharmaceutically acceptable prodrug is a compound having a group thatcan be converted into an amino group, a hydroxyl group, a carboxylgroup, or the like through solvolysis or under physiological conditions.Examples of the group forming the prodrug include the groups describedin Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research andDevelopment” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design,163-198.

Furthermore, the salt of the compound of the formula (I) is apharmaceutically acceptable salt of the compound of the formula (I) andmay form an acid addition salt or a salt with a base depending on thekind of substituents. Specific examples thereof include acid additionsalts with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, and with organic acids such as formic acid, acetic acid, propionicacid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleicacid, lactic acid, malic acid, mandelic acid, tartaric acid,dibenzoyltartaric acid, ditolyltartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, andsalts with inorganic bases such as sodium, potassium, magnesium,calcium, aluminum, and the like or organic bases such as methylamine,ethylamine, ethanolamine, lysine, ornithine, and the like, salts withvarious amino acids or amino acid derivatives such as acetylleucine andthe like, ammonium salts, etc.

In addition, the present invention also includes various hydrates orsolvates, and polymorphic crystalline substances of the compound of theformula (I) and a salt thereof. In addition, the present invention alsoincludes compounds labeled with various radioactive or non-radioactiveisotopes.

(Preparation Methods)

The compound of the formula (I) and a salt thereof can be prepared usingthe characteristics based on the basic structure or the type ofsubstituents thereof and by applying various known synthesis methods.During the preparation, replacing the relevant functional group with asuitable protective group (a group that can be easily converted into therelevant functional group) at the stage from starting material to anintermediate may be effective depending on the type of the functionalgroup in the production technology in some cases. The protective groupfor such a functional group may include, for example, the protectivegroups described in “Greene's Protective Groups in Organic Synthesis(4^(th) edition, 2006)”, P. G. M. Wuts and T. W. Greene, and one ofthese may be selected and used as necessary depending on the reactionconditions. In this kind of method, a desired compound can be obtainedby introducing the protective group, by carrying out the reaction and byeliminating the protective group as necessary.

In addition, the prodrug of the compound of the formula (I) can beprepared by introducing a specific group or by carrying out the reactionusing the obtained compound of the formula (I) at the stage from astarting material to an intermediate, just as in the case of theabove-mentioned protective group. The reaction can be carried out usingmethods known to those skilled in the art, such as ordinaryesterification, amidation, dehydration, and the like.

Hereinbelow, the representative preparation methods for the compound ofthe formula (I) will be described. Each of the production processes mayalso be carried out with reference to the References appended in thepresent description. Further, the preparation methods of the presentinvention are not limited to the examples as shown below.

(Production Process 1)

The compound (I) of the present invention can be obtained by thecondensation of a compound (4) with a carboxylic acid (5) or aderivative thereof.

For the reaction, the compound (4) and the carboxylic acid (5) inequivalent amounts, or either thereof in an excess amount are used, anda mixture thereof is stirred in a range of from cooling to heating,preferably at a temperature from −20° C. to 60° C., usually for about0.1 hours to 5 days, in a solvent which is inert to the reaction, in thepresence of a condensing agent. The solvent as used herein is notparticularly limited, but examples thereof include aromatic hydrocarbonssuch as benzene, toluene, xylene, and the like, halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane, chloroform, and the like,ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane,and the like, DMF, DMSO, EtOAc, acetonitrile, or water, and a mixturethereof. Examples of the condensing agent include, but are not limitedto, CDI, diphenylphosphonyl azide, phosphorus oxychloride, and WSC(Water-Soluble Condensing agent, trademark,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide,and the like). It may be in some cases preferable for the reaction touse an additive (for example, 1-hydroxybenzotriazole). It is in somecases advantageous for smooth progress of the reaction to carry out thereaction in the presence of organic bases such as triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, DBU, DMAP, and the like,or inorganic bases such as potassium carbonate, sodium carbonate,potassium hydroxide, and the like.

Furthermore, it is also possible to use a method in which a reactivederivative of the carboxylic acid (5) is used, and reacted with thecompound (4). Examples of the reactive derivative of the carboxylic acidinclude acid halides that can be obtained by the reaction with ahalogenating agent such as phosphorus oxychloride, thionyl chloride, andthe like, mixed acid anhydrides that can be obtained by the reactionwith isobutyl chloroformate or the like, active esters that can beobtained by condensation with 1-hydroxybenzotriazole or the like, etc.The reaction of the reactive derivative with the compound (4) can becarried out in a range of from cooling to heating, and preferably from−20° C. to 60° C., in a solvent which is inert to the reaction, such ashalogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.

DOCUMENTS

-   “Organic Functional Group Preparations”, S. R. Sandler and W. Karo,    2^(nd) edition, Vol. 1, Academic Press Inc., 1991-   The Chemical Society of Japan, “Courses in Experimental Chemistry    (5^(th) edition)” Vol. 16 (2005) (Maruzen)

(Production Process 2)

The compound (I) of the present invention can be obtained by thecondensation of a compound (16) with a compound (7).

The present reaction can be carried out using the reaction condition asdescribed in (Production Process 1).

(Other Production Processes)

Furthermore, various substituents in the formula (I) can also be easilyconverted into other functional groups by using the compound (I) of thepresent invention as a starting material by means of reactions apparentto a skilled person in the art, or modified methods thereof. Thereaction can be carried out by any combination of the processes that canbe usually employed by a skilled person in the art, such as hydrolysis,alkylation, halogenation, hydrogenation, and the like. Examples thereofare presented below.

(Production Process 3)

(wherein R is R^(Z11) or NR^(Z13)R^(Z14).)

The compound (1-1) of the present invention can be obtained by thesubstitution reaction of a compound (18) and a compound (17).

In this reaction, the compound (18) and the compound (17) in equivalentamounts, or either thereof are used, a mixture thereof is stirred in arange of from cooling to heating and refluxing, preferably at 0° C. to200° C., and preferably at 150° C. to 200° C., usually for 0.1 hours to5 days in a solvent which is inert to the reaction or without a solvent.It is in some cases advantageous for smooth progress of the reaction tocarry out the reaction under irradiation with microwaves. The solventused herein is not particularly limited, but examples thereof includealcohols such as methanol, ethanol, tert-butanol, and the like, aromatichydrocarbons such as benzene, toluene, xylene, and the like, ethers suchas diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and thelike, halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide,dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof.It may be advantageous in some cases for the smooth progress of thereaction to carry out the reaction in the presence of an organic basesuch as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine,and the like, or an inorganic base such as sodium tert-butoxide,potassium carbonate, sodium bis(methylsilyl)amide, sodium carbonate,potassium hydroxide, and the like.

Furthermore, the reaction may be carried out using a catalyst which isnot particularly limited, but includes catalysts used for an Ullmannreaction, a Buchwald-Hartwig reaction, or the like. The catalyst as usedherein is not particularly limited, but a suitable combination oftris(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine)palladium, or the like with4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (Xantphos),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and thelike can be used.

DOCUMENTS

-   “Organic Functional Group Preparations”, S. R. Sandler and W. Karo,    2^(nd) edition, Vol. 1, Academic Press Inc., 1991-   The Chemical Society of Japan, “Courses in Experimental Chemistry    (5^(th) edition)” Vol. 14 (2005) (Maruzen)-   Synthesis 2006, 4, 629-632

(Starting Material Synthesis 1)

First, the compound (1) can be converted to the compound (2), forexample, by reacting a brominating agent used for a Wohl-Zieglerreaction, such as N-bromoacetamide and N-bromosuccinimide in thepresence of a radical initiator.

In this reaction, the compound (1) is treated with a brominating agentin a range of from cooling to heating, preferably at 0° C. to 150° C.,and preferably at 0° C. to 120° C., usually for 0.1 hours to 5 hours,and preferably 1 to 2 hours, in a solvent which is inert to thereaction. It is in some cases advantageous for smooth progress of thereaction to carry out the reaction under irradiation with microwaves.

The solvent used herein is not particularly limited, but examplesthereof include aromatic hydrocarbons such as benzene, toluene, xylene,and the like, halogenated hydrocarbons such as 1,2-dichloroethane,chloroform, carbon tetrachloride, and the like, and a mixture thereof.Further, examples of the radical initiator are not particularly limited,but include benzoyl peroxide and azoisobutyronitrile.

Next, the compound (2) can be converted to the compound (4) by thenucleophilic substitution reaction of the amine compound (3).

In this reaction, the compound (2) and the amine compound (3) inequivalent amounts, or either thereof in an excess amount are used, anda mixture thereof is stirred in a range of from cooling to heating andrefluxing, and preferably at −20° C. to 80° C., usually for 0.1 hours to5 days in a solvent which is inert to the reaction or without a solvent.The solvent used herein is not particularly limited, but examplesthereof include aromatic hydrocarbons such as benzene, toluene, xylene,and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform, and the like, DMF,DMSO, EtOAc, acetonitrile, and a mixture thereof. It may be advantageousin some cases for the smooth progress of the reaction to carry out thereaction in the presence of an organic base such as triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, and the like, or aninorganic base such as potassium carbonate, sodium carbonate, potassiumhydroxide, and the like.

(Starting Material Synthesis 2)

(wherein R^(Prot) represents lower alkyl or aryl.)

The compound (10) can be prepared by treating the compound (8) using thesame condition as for the reaction described in (Starting MaterialSynthesis 1).

Next, the compound (11) can be prepared by the reaction of the compound(10) and the carboxylic acid (5) using the same condition as for thereaction described in (Production Process 1) as described above.

The compound (7) can be obtained by the hydrolysis reaction of thecompound (11). Herein, the hydrolysis reaction can be carried out withreference to documents such as Greene, and the like.

The compound (18) can be obtained by the condensation reaction of thecompound (7) with NH₃ using the same condition as for the reactiondescribed in (Production Process 1) as described above.

DOCUMENTS

-   “Organic Functional Group Preparations”, S. R. Sandler and W. Karo,    2^(nd) edition, Vol. 1, Academic Press Inc., 1991-   The Chemical Society of Japan, “Courses in Experimental Chemistry    (5^(th) edition)” Vol. 14 (2005) (Maruzen)-   “Greene's Protective Groups in Organic Synthesis (4^(th) edition,    2006)”, P. G. M. Wuts and T. W. Greene

(Starting Material Synthesis 3)

(wherein W represents a leaving group, and R^(Prot) represents loweralkyl or aryl.)

The compound (15) is prepared by three steps from the isocyanate (12).Here, examples of the leaving group X include halogen.

First, the compound (13) can be obtained by the addition reaction of theisocyanate (12) and an alcohol, R^(Prot)'OH.

In this reaction, a mixture of the isocyanate (12) and the alcohol,R^(Prot)OH in an equivalent amount or in an excess amount are reacted ina range of from cooling to heating, and preferably at −50° C. to 100°C., and preferably at −20° C. to 90° C., usually for 0.1 hours to 10hours, and preferably for about 1 hour to 3 hours, in a solvent which isinert to the reaction or without a solvent. The solvent used in thisstep is not particularly limited, but examples thereof includehalogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane,chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran,dioxane, dimethoxyethane, and the like, alcohols such as MeOH, EtOH,tert-butanol, and the like, DMF, DMSO, EtOAc, water, and acetonitrile.

Next, the compound (13) can be converted to the compound (14) by thenucleophilic substitution reaction of an amine, R¹⁰¹R¹⁰²NH, using thesame method as for (Starting Material Synthesis 1) as described above.

Lastly, an aminosulfonamide compound (15) can be obtained by thedeprotection reaction of the compound (14) with reference to documentssuch as Greene, and the like.

DOCUMENT

-   Pamphlet of International Publication WO 2002/053557

The compounds of the formula (I) can be isolated and purified as theirfree compounds, salts, hydrates, solvates, or polymorphic crystallinesubstances thereof. The salts of the compound of the formula (I) can beprepared by carrying out the treatment of a conventional salt formingreaction.

Isolation and purification are carried out by employing ordinarychemical operations such as extraction, fractional crystallization,various types of fractional chromatography, and the like.

Various isomers can be prepared by selecting an appropriate startingcompound or separated by using the difference in the physicochemicalproperties between the isomers. For example, the optical isomers can beobtained by means of a general method for designing optical resolutionof racemic products (for example, fractional crystallization forinducing diastereomer salts with optically active bases or acids,chromatography using a chiral column or the like, and others), andfurther, the isomers can also be prepared from an appropriate opticallyactive starting compound.

The pharmacological activity of the compound of the formula (I) wasconfirmed by the tests shown below.

Test Example 1 Antagonistic Action of Compound of Formula (I) on HumanLPA1

The antagonistic action on a human LPA 1 was evaluated with an index ofan inhibitory action on the LPA-stimulated increase in intracellularcalcium ion concentration, using human LPA 1-CHO cells [cells in whichhuman LPA1 receptors are stably expressed in CHO (dhfr gene-deficient)cell lines].

Establishment of human LPA1-CHO cells was performed based on the basicgenetic engineering techniques.

The established cells were maintained by passage in a nucleic acid-freeα-MEM medium (Invitrogen) containing 10% FBS, 1% penicillin/streptomycin(Invitrogen), and 100 nM methotrexate, and before experiment, the mediumwas replaced with a medium that had been reduced to 1% of the PBSconcentration, then seeded in 96-well plates to 1.5×10e⁵ cells/100μL/well, and incubated overnight.

On the day of experiment, a 0.5 μM Fluo-4 solution [a solution preparedby adding 20 mM HEPES (Sigma), 250 mM probenecid (Nacalai Tesque), 0.05%BSA, 0.5 μM Fluo-4 AM (Dojindo Laboratories), and 0.1% Pluronic F217(Molecular Probe Co.) to a Hanks Balanced Solt Solution (Invitrogen)]was, and loaded Fluo-4 on the cells by incubating for 2 hours at roomtemperature.

After loading Fluo-4, the Fluo-4 solution was replaced with a reactionsolution [a solution obtained by adding 20 mM HEPES, 250 mM probenecid,and 0.05% BSA to a Hanks Balanced Solt Solution], and then measurementwas performed using a device for measuring an intracellular calciumconcentration (FLIPR tetra, Molecular Devices Inc.).

A reaction solution in which the compound of the formula (I) (with afinal concentration of 0.1 nM to 10 μM) had been dissolved was added toeach of the wells, the signals were measured over time for 4 minutes,then a reaction solution in which LPA (final concentration 100 nM) hadbeen dissolved was added thereto, and the signals were measured overtime for 2 minutes. The difference between the maximum and minimumresponse during one minute from addition of LPA was calculated. Theinhibitory activity was calculated, with a response when LPA only (notincluding the compound) was added was taken as 0% inhibition, and aresponse when a reaction solution not including both of the compound andLPA was added was taken as 100% inhibition. Then the 50% inhibitoryconcentration was calculated as an IC₅₀ value (nM). The results areshown in Table 1.

Human LPA1-CHO cells used in the present test were the cells with thesame sequence as described in the pamphlet of International PublicationWO 99/19513 were used. Further, Ex represents Example No. as denotedbelow.

TABLE 1 Ex IC₅₀ (nM) 5 7.8 69 8.8 22 24 27 14 56 29 62 11 71 16 79 16 8917 108 11 109 22 110 11 111 6.6 113 12 115 16 121 19 123 7.5 126 20 1317.2 134 25 137 9.9 145 23 147 16 153 21 154 34 156 15 167 12 168 17 17034 175 23 176 24 200 33 208 40 233 22 266 65 272 44 277 12 283 29 285 32290 33

Further, as a result of the present test on the compound of Example 10(5) in the pamphlet of WO 2004/031118, the IC₅₀ value of the relevantcompound was 99 nM. Accordingly, it became apparent that the compound ofthe present invention has an excellent LPA1 receptor antagonisticaction, as compared with the relevant compound.

Test Example 2 Inhibitory Action of Compound of Formula (I) onLPA-Induced Increase in Urethral Pressure in Rats Under Anesthesia (withIntravenous Administration at 0.1 mg/kg)

Male Wistar rats (Charles River, 9- to 12-week old) were anesthetizedwith urethane (1.2 g/kg ip), and held in the supine position on anoperating table kept at 37° C. The lower abdominal portion wasmidline-incised and the bladder was thus exposed. A small portion of thebladder apex was incised, a microchip pressure transducer (Millar) wasinserted antegrade, and then placed in the urethra, and the urethralpressure was recorded continuously. In addition, a cannula foradministration of a drug was placed into the femoral vein. After about 1hour of stabilization, the compound of formula (I) (0.1 mg/kg) wasadministered intravenously. After 5 minutes, LPA (1-oleoyl) wasadministered intravenously at 3 mg/kg, and the changes in the urethralpressure were recorded. The inhibitory rates (%) of the compound of theformula (I) on the LPA-stimulated increase in the urethral pressurecompared with those after administration of the solvent of the compoundof the formula (I) were calculated. The results are shown in Table 2.

TABLE 2 Inhibitory rate Ex (%) 69 33 9 28 63 28 71 18 111 56 123 39 13039 131 38 132 42 137 17 145 16 153 21 154 28 162 21 167 35 200 31 208 14233 38 266 15 277 42

Test Example 3 Estimation of Concentration in Plasma (2Hours after OralAdministration) after Administration of Compound of Formula (I) in RatsUsing Ex Vivo Bioassay Method

The concentration in the plasma after administration of the compound ofthe formula (I) in rats was estimated according to a bioassay method.That is, test compounds were orally administered to male Wistar rats(Charles River, 6-week old, and fasted), and after a certain period oftime, blood was collected from the ophthalmic basilar plexus to giveplasma. The compound was extracted from the plasma, and the extractedcompound was dissolved in a certain amount of DMSO. Further, for thestandard curve, the plasma in which the compounds at variousconcentrations had been dissolved was prepared separately, and the sameextraction procedure was conducted.

The inhibitory action on the LPA-stimulated increase in theintracellular calcium ion concentration in LPA1-expressing cells in theDMSO extract was measured, and the plasma concentration in theindividual after administration was estimated from the standard curve.The results are shown in Table 3.

TABLE 3 Concentration in plasma Ex (μM) 9 8.3 22 1.3 27 6.5 56 1.8 712.1 89 2.4 100 6.7 126 8.9 134 1.4 145 5.6 153 5.2 154 3.1 156 2.1 1701.8 171 2.2 176 4.5

As a result of the test, it was confirmed that the compound of theformula (I) has an excellent LPA receptor antagonistic action and anexcellent inhibitory action on an LPA-induced increase in the urethralpressure in rats under anesthesia. Further, by an ex vivo bioassaymethod, it was confirmed that the compound of the formula (I) hasexcellent oral absorption, and thus, it can be used for treatment ofdiseases caused by LPA, or the like.

A pharmaceutical composition containing one or or two more kinds of thecompound of the formula (I) or a salt thereof as an active ingredientcan be prepared using excipients that are usually used in the art, thatis, excipients for pharmaceutical preparation, carriers forpharmaceutical preparation, and the like according to the methodsusually used.

Administration can be accomplished either by oral administration viatablets, pills, capsules, granules, powders, solutions, and the like, orparenteral administration, such as injections such as intraarticular,intravenous, and intramuscular injections, suppositories, ophthalmicsolutions, eye ointments, transdermal liquid preparations, ointments,transdermal patches, transmucosal liquid preparations, transmucosalpatches, inhalers, and the like.

The solid composition for use in the oral administration is used in theform of tablets, powders, granules, or the like. In such a solidcomposition, one or more active ingredient(s) are mixed with at leastone inactive excipient. In a conventional method, the composition maycontain inactive additives, such as a lubricant, a disintegrating agent,a stabilizer, or a solubilization assisting agent. If necessary, tabletsor pills may be coated with sugar or a film of a gastric or entericcoating substance.

The liquid composition for oral administration contains pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, or thelike, and also contains generally used inert diluents, for example,purified water or ethanol. In addition to the inert diluent, the liquidcomposition may also contain auxiliary agents, such as a solubilizationassisting agent, a moistening agent, and a suspending agent, sweeteners,flavors, aromatics, or antiseptics.

The injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. The aqueous solventincludes, for example, distilled water for injection and physiologicalsaline. Examples of the non-aqueous solvent include alcohols such asethanol. Such a composition may further contain a tonicity agent, anantiseptic, a moistening agent, an emulsifying agent, a dispersingagent, a stabilizer, or a solubilizing aid. These are sterilized, forexample, by filtration through a bacteria retaining filter, blending ofa bactericide, or irradiation. In addition, these can also be used bypreparing a sterile solid composition, and dissolving or suspending itin sterile water or a sterile solvent for injection prior to its use.

The agent for external use includes ointments, plasters, creams,jellies, poultices, sprays, lotions, eye drops, eye ointments, and thelike. The agents contain generally used ointment bases, lotion bases,aqueous or non-aqueous liquid preparations, suspensions, emulsions, andthe like.

As the transmucosal agents such as an inhaler, a transnasal agent, andthe like, those in the form of a solid, liquid, or semi-solid state areused, and can be prepared in accordance with a conventionally knownmethod. For example, a known excipient, and also a pH adjusting agent,an antiseptic, a surfactant, a lubricant, a stabilizer, a thickeningagent, or the like may be appropriately added thereto. For theiradministration, an appropriate device for inhalation or blowing can beused. For example, a compound may be administered alone or as a powderof formulated mixture, or as a solution or suspension in combinationwith a pharmaceutically acceptable carrier, using a known device orsprayer, such as a measured administration inhalation device, and thelike. A dry powder inhaler or the like may be for single or multipleadministration use, and a dry powder or a powder-containing capsule maybe used. Alternatively, this may be in a form such as a pressurizedaerosol spray which uses an appropriate ejection agent, for example, asuitable gas such as chlorofluoroalkane, carbon dioxide, and the like.

In oral administration, the daily dose is generally from about 0.001 to100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to10 mg/kg, per body weight, administered in one portion or in 2 to 4divided portions. In the case of intravenous administration, the dailydose is suitably administered from about 0.0001 to 10 mg/kg per bodyweight, once a day or two or more times a day. In addition, atransmucosal agent is administered at a dose from about 0.001 to 100mg/kg per body weight, once a day or two or more times a day. The doseis appropriately decided in response to the individual case by takingthe symptoms, the age, and the gender, and the like into consideration.

The compound of the formula (I) can be used in combination with varioustherapeutic or prophylactic agents for the diseases for which thecompound of the formula (I) is considered to be effective, as describedabove. The combined preparation may be administered simultaneously, orseparately and continuously, or at a desired time interval. Thepreparations to be administered simultaneously may be a blend, or may beprepared individually.

EXAMPLES

Hereinbelow, the preparation methods for the compound of the formula (I)will be described in more detail with reference to Examples. Further,the present invention is not limited to only the preparation methods ofthe specific Examples and Preparation Examples below, but the compoundof the formula (I) can be prepared by a combination of the preparationmethods or a method apparent to a person skilled in the art.

Moreover, the following abbreviations may be used in some cases in theExamples, Preparation Examples, and Tables as described later.

Rf: Preparation Example No.,

Ex: Example No.,

Data: Physicochemical data,

ESI+: representing m/z values in ESI-MS (positive ions), andrepresenting [M+H]⁺ peaks unless otherwise specified,

ESI−: representing m/z values in ESI-MS (negative ions), andrepresenting [M−Hf]⁻ peaks unless otherwise specified,

APCI+: representing m/z values in APCI-MS (positive ions), andrepresenting [M+H]⁺ peaks unless otherwise specified,

APCI−: representing m/z values in APCI-MS (negative ions), andrepresenting [M−H]⁻ peaks unless otherwise specified,

FAB+: representing m/z values in FAB-MS (positive ions), andrepresenting [M+H]⁺ peaks unless otherwise specified,

FAB−: representing m/z values in FAB-MS (negative ions), andrepresenting [M−H]⁻ peaks unless otherwise specified,

EI+: representing m/z values in EI-MS (positive ions), and representing[M]⁺ peaks unless otherwise specified,

CI+: representing m/z values in CI-MS (negative ions), and representing[M+H]⁺ peaks unless otherwise specified,

NMR-DMSO-d₆: δ (ppm) in ¹H NMR in DMSO-d₆,

NMR-CDCl₃: δ (ppm) in ¹H NMR in CDCl₃,

Structure: Structural formula,

Syn: Preparation method (in which the numeral shows that the compound isprepared by the same preparation method as the compound having theExample No. and R prefixed before the numeral shows that the compound isprepared by the same preparation method as the compound having thePreparation Example No.),

D-Arg: D-arginate,

HCl: hydrochloride,

brine: saturated brine,

DMSO: dimethylsulfoxide,

THF: tetrahydrofuran,

EtOH: ethanol,

DME: 1,2-dimethoxyethane,

DMF: N,N-dimethylformamide,

MeOH: methanol,

CHCl₃: chloroform,

CDI: 1,1′-carbonyldiimidazole,

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene,

DEAD: diethyl azodicarboxylate,

DMAP: 4-dimethylaminopyridine,

HOBT: 1-hydroxybenzotriazole,

WSCD HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,

TBAF: tetrabutylammonium fluoride,

NBS: N-bromosuccinimide,

AIBN: 2,2′-azobis(isobutyronitrile),

LHMDS: lithium bis(trimethylsilyl)amide,

Pd (PPh₃)₄: tetrakis(triphenylphosphine) palladium (0),

Zn(CN)₂: dicyanozinc,

ADDP: 1,1′-(azodicarbonyl)dipiperidine,

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,

DBAD: di-tert-butylazodicarboxylate,

DAST: (diethylamino)sulfur trifluoride,

MgSO₄: anhydrous magnesium sulfate,

Na₂SO₄: anhydrous sodium sulfate,

n-Bu: normal butyl,

M: mol/L.

Preparation Example 1

tert-Butyl 4-formyl-3,5-dimethoxybenzoate (1.43 g) and anisole (0.85 g)were added to methylene chloride (30 mL), and trifluoroacetic acid (15mL) was slowly added dropwise thereto under ice-cooling, followed bystirring at room temperature for about 2 hours. The solvent wasevaporated under reduced pressure and an appropriate amount of ice waterwas poured into the obtained residue. The resulting pale orangeprecipitate was collected by filtration and dried to prepare4-formyl-3,5-dimethoxybenzoic acid (1.11 g).

Preparation Example 2

tert-Butyl5-(acetoxymethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(150 mg) was added to methylene chloride (2 mL), followed byice-cooling. To this mixture was slowly added dropwise trifluoroaceticacid (0.67 mL), followed by stirring at room temperature for about 14hours. The solvent was evaporated under reduced pressure, and anappropriate amount of toluene was poured into the obtained residue. Thesolvent was evaporated again under reduced pressure. This procedure wasrepeated twice and azeotroped with trifluoroacetic acid to prepare5-(acetoxymethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (135 mg).

Preparation Example 3

Ethyl 3,5-dimethoxy-4-vinylbenzoate (150 mg) was added to an EtOH/THF(1:1) solution (4 mL), and a 1 M aqueous sodium hydroxide solution (1.25mL) was added dropwise thereto, followed by stirring at room temperaturefor about 12 hours. The solvent was evaporated under reduced pressure,and to the obtained residue was added purified water. To this mixturewas added dropwise 1 M hydrochloric acid (1.25 mL) under ice-cooling,and the precipitated white solid was collected by filtration and driedunder reduced pressure to prepare 3,5-dimethoxy-4-vinylbenzoic acid (111mg).

Preparation Example 4

Ethyl2-{[(tert-butoxycarbonyl)(3-phenylpropyl)aminomethyl]methyl}-1,3-thiazole-4-carboxylate(1.27 g) was added to a THF/MeOH (2:1) solution (13.2 mL), and a 1 Maqueous sodium hydroxide solution (4.4 mL) was added dropwise thereto,followed by stirring at room temperature for about 2 hours. Ice water(about 50 g) including 1 M hydrochloric acid (7 mL) was poured into thereaction mixture, followed by extraction with an appropriate amount ofethyl acetate twice. The organic layer was washed with brine and thendried over MgSO₄, and the solvent was evaporated to prepare2-{[tert-butoxycarbonyl)(3-phenylpropyl)aminomethyl]methyl}-1,3-thiazole-4-carboxylicacid (1.15 g).

Preparation Example 5

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(3.5 g) was added to a THF/EtOH (2:1) solution (45 mL), and a 1 Maqueous sodium hydroxide solution (15 mL) was added dropwise thereto,followed by stirring at room temperature for about 2 hours. Anappropriate amount of a saturated aqueous ammonium chloride solutionincluding 1 M hydrochloric acid (30 mL) and ice water were poured intothe reaction mixture, followed by extraction with ethyl acetate twice.The obtained organic layer was washed with brine and dried over MgSO₄,and the solvent was evaporated under reduced pressure to obtain a whitefoam. The obtained white foam was crystallized from a small amount ofethyl acetate-hexane (3:1), washed with diethyl ether, and collected byfiltration to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (3.11 g) as a white powder.

Preparation Example 6

tert-Butyl {[(2-fluoroethyl)(methyl)amino]sulfonyl}carbamate (412 mg)and trifluoroacetic acid (5 mL) were added to methylene chloride (5 mL),followed by stirring at room temperature for about 1 hour, and then thesolvent was evaporated under reduced pressure to prepareN-(2-fluoroethyl)-N-methylsulfamide (156 mg).

Preparation Example 7

N-Methyl-N-[2-(methylsulfanyl)ethyl]sulfamide was prepared fromN-methyl-2-(methylsulfanyl)ethanamine by carrying out the same reactionsas in Preparation Example 54 and Preparation Example 6, successively.

Preparation Example 8

1-(5-Methoxypyridin-2-yl)cyclopropanecarbonitrile (100 mg) and a 5 Maqueous potassium hydroxide solution (2 mL) were added to ethyleneglycol (2 mL), followed by heating at 120° C. overnight. To the reactionmixture was added an appropriate amount of ice water, and 1 Mhydrochloric acid was further added thereto to adjust the mixture to beweakly acidic, followed by extraction with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄, and then concentratedunder reduced pressure to prepare1-(5-methoxypyridin-2-yl)cyclopropanecarboxylic acid (55 mg).

Preparation Example 9

4-Formyl-3,5-dimethoxybenzoic acid (1.38 g) was added to DMF (12 mL),followed by adding potassium carbonate (1.82 g) and methyl iodide (0.61mL) sequentially and stirring at room temperature for about 15 hours.Ice water (120 mL) was poured into the reaction mixture, followed bystirring for about 30 minutes, and then the resulting insoluble materialwas collected by filtration while washing with purified water, and thendried under reduced pressure at 40° C. to prepare methyl4-formyl-3,5-dimethoxybenzoate (1.24 g).

Preparation Example 10

5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (0.83 g) was added to benzene (10 mL), and 1,1-di-tert-butoxyN,N-dimethylmethane (2 mL) was further slowly added dropwise thereto,followed by heating at 70 to 80° C. for about 30 minutes. Subsequently,0.5 equivalents of 1,1-di-tert-butoxy-N,N-dimethylmethane was addedagain thereto, followed by further heating for 30 minutes. The reactionmixture was left to be cooled, and ethyl acetate was added thereto. Themixture was washed with a saturated aqueous sodium chloride solutionincluding a small amount of 1 M hydrochloric acid, and then the organiclayer was dried over MgSO₄. The residue obtained by evaporating thesolvent was purified by silica gel column chromatography (ethylacetate:hexane=2:1) to prepare tert-butyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(500 mg).

Preparation Example 11

Ethyl 4-bromo-3,5-dimethoxybenzoate (2.13 g) was added to toluene (60mL), and subsequently, tris(2-methylphenyl)phosphine (0.9 g),(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one.palladium (3:2) (1.35 g), andtributyl(vinyl)tin (2.57 g) were sequentially added thereto, followed byheating at 140° C. for about 36 hours. The reaction mixture was left tobe cooled, and then an appropriate amount of ethyl acetate and 0.2 Mhydrochloric acid were poured thereinto. The resulting insolublematerial was removed by filtration through Celite, and then subjected toa liquid separation operation to separate the organic layer. The organiclayer was sequentially washed with an appropriate amount of an aqueoussodium hydrogen carbonate solution and brine, and dried over MgSO₄, andthen the solvent was evaporated. The obtained residue was purified bysilica gel column chromatography (ethyl acetate:hexane=9:1) to prepareethyl 3,5-dimethoxy-4-vinylbenzoate (1.2 g).

Preparation Example 12

Ethyl 4-bromo-3,5-dimethoxybenzoate (2.0 g) was added towater-containing toluene (toluene (30 mL), purified water (1.56 mL)),and subsequently, cyclopropyl boric acid (772 mg),tricyclohexylphosphine (194 mg), potassium phosphate tribasic (5.14 g),and palladium(II) acetate (78 mg) were sequentially added thereto,followed by heating at 100° C. for about 12 hours. The reaction mixturewas left to be cooled, and then the insoluble material was collected byfiltration by washing it an appropriate amount of ethyl acetate, and thefiltrate was sequentially washed with purified water and brine. Theorganic layer was dried over MgSO₄, the solvent was evaporated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:10) to prepare ethyl4-cyclopropyl-3,5-dimethoxybenzoate (1.24 g).

Preparation Example 13

Ethyl5-bromo-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(700 mg) was added to DMF (20 mL), and subsequently, Pd (PPh₃)₄ (720 mg)and Zn(CN)₂ (146 mg) were sequentially added thereto, followed bystirring at 90° C. for 2 days. Further, Pd(PPh₃)₄ and Zn(CN)₂ were eachadded in the amount of 0.5 equivalents, followed by heating at 100° C.until the starting material was lost. The reaction mixture was left tobe cooled, and then the reaction mixture was diluted with an appropriateamount of ethyl acetate. The insoluble material was collected byfiltration. The filtrate was sequentially washed with an appropriateamount of a saturated aqueous sodium hydrogen carbonate solution andpurified water, and the organic layer was dried over MgSO₄ and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:1) toprepare ethyl5-cyano-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(467 mg).

Preparation Example 14

According to the method of Falck, et al. (Tetrahedron Lett., 1994 35,5997), methyl 3,5-dimethoxy-4-(hydroxymethyl)benzoate (0.34 g) and ADDP(0.76 g) were added to anhydrous benzene (15 mL), and subsequently,tri-n-butylphosphine (0.74 mL) was slowly added dropwise thereto,followed by stirring at room temperature for about 15 minutes. To thismixture was added dropwise an excess amount of trifluoroethanol (0.86mL), followed by stirring at room temperature for about 13 hours. Thereaction mixture was evaporated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:3) to prepare methyl3,5-dimethoxy-4-[(2,2,2-trifluoroethoxy)methyl]benzoate (0.45 g) as awhite solid.

Preparation Example 15

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate(300 mg) was added to methyl iodide (9 mL), and subsequently, silver(I)oxide (149 mg), and MgSO₄ (239 mg) were added thereto, followed bystirring at room temperature for about 2 days in a sealed tube. To thereaction mixture was added silver(I) oxide (75 mg), followed by stirringat room temperature for additional 3 days. The insoluble material of thereaction mixture was collected by filtration through Celite whilewashing with an appropriate amount of CHCl₃. The filtrate was washedwith water and dried over MgSO₄, and then the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:1) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(methoxymethyl)-1,3-thiazole-4-carboxylate(248 mg).

Preparation Example 16

Ethyl 3,5-dimethoxy-4-vinylbenzoate (1.3 g) was added to MeOH (39 mL),followed by cooling to −78° C. To the mixture was added an appropriateamount of CHCl₃, followed by stirring for 20 minutes under an ozoneatmosphere while maintaining the same temperature. Thereafter, thereaction mixture was held under an oxygen atmosphere, and the reactionmixture was added dimethyl sulfide (0.48 mL), followed by stirring at−78° C. for 30 minutes. To the reaction mixture was added an appropriateamount of ethyl acetate, followed by sequentially washing with anaqueous sodium hydrogen carbonate solution and brine. The obtainedorganic layer was dried over Na₂SO₄, and then the solvent wasevaporated. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=4:1) to prepare ethyl3,5-dimethoxy-4-formylbenzoate (1.0 g) as a white solid.

Preparation Example 17

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-vinyl-1,3-thiazole-4-carboxylate(2.0 g) was added to an acetone/tert-butanol/water (1:1:1) solution (45mL), and subsequently a 0.1 M osmium tetraoxide (1.97 L) and sodiumperiodate (1.85 g) were sequentially added thereto, followed by stirringat room temperature for about 14 hours. About 200 g of ice water waspoured into the reaction mixture, followed by extraction with anappropriate amount of ethyl acetate several times. The organic layer waswashed with brine and dried over MgSO₄, and then the solvent wasevaporated. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=3:2) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-formyl-1,3-thiazole-4-carboxylate(1.83 g).

Preparation Example 18

N-{[4-(Hydroxymethyl)-1,3-thiazol-2-yl]methyl}-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide(0.75 g) and triethylamine (0.71 mL) were added to methylene chloride(7.5 mL), and a mixture of a sulfur trioxide-pyridine complex (0.83 g)and DMSO (1.5 mL) was slowly added dropwise thereto under ice-cooling,followed by stirring under ice-cooling about 4 hours. A small amount ofa 1 M hydrochloric acid solution and a saturated aqueous ammoniumchloride solution were poured into the reaction mixture, followed byextraction with CHCl₃. The organic layer was washed with water anddried, and then the solvent was evaporated. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=3:1)to prepareN-[(4-formyl-1,3-thiazol-2-yl)methyl]-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide(0.69 g).

Preparation Example 19

2-(Chloromethyl)-5-methoxypyridine (125 mg) was added to DMSO (5 mL),and subsequently, an aqueous potassium cyanide solution (potassiumcyanide (155 mg) and water (1 mL)) was added thereto, followed bystirring at room temperature overnight. An appropriate amount ofpurified water was poured into the reaction mixture under ice-cooling,followed by extraction with ethyl acetate. The obtained organic layerwas sequentially washed with purified water and brine, and dried overMgSO₄, and then the solvent was evaporated under reduced pressure toprepare (5-methoxypyridin-2-yl)acetonitrile (110 mg).

Preparation Example 20

To a mixture of (5-methoxypyridin-2-yl)acetonitrile (0.11 mg),1-bromo-2-chloroethane (0.2 mL), and N-benzyl-N,N,N-triethylammoniumchloride (20 mg) was slowly added dropwise a 50% aqueous sodiumhydroxide solution (2 mL) under ice-cooling, followed by stirring atroom temperature for about 5 hours. Ice water was poured into thereaction mixture, followed by extraction with diethyl ether. The organiclayer was washed with brine, dried over Na₂SO₄, and then concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:2) to prepare1-(5-methoxypyridin-2-yl)cyclopropanecarbonitrile (100 mg) as a whitesolid.

Preparation Example 21

tert-Butyl 4-formyl-3,5-dimethoxybenzoate (0.3 g) was added to methylenechloride (10 mL), and subsequently, DAST (0.25 mL) was added dropwisethereto at 0° C., followed by stirring at room temperature overnight. Tothe reaction mixture was carefully added a saturated aqueous sodiumhydrogen carbonate solution, followed by extraction with CHCl₃. Theorganic layer was washed with brine and dried over MgSO₄, and then thesolvent was evaporated. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=7:3 to 5:5) to obtain acolorless oily substance. The obtained oily substance was dissolved in 4M hydrochloric acid/ethyl acetate (10 mL), followed by stirring at roomtemperature for 3 hours. Thereafter, the solvent was evaporated toprepare 4-(difluoromethyl)-3,5-dimethoxybenzoic acid (0.22 g) as a whitesolid.

Preparation Example 22

The following products were prepared with a partial modification of themethod of Liu, et al. (Synthesis, 2001 14, 2078-2080). Ethyl(2-methyl-1,3-thiazol-4-yl)carboxylate (25 g) was added to carbontetrachloride (500 mL), and subsequently, NBS (53 g), and benzoylperoxide (4.7 g) (wetted with 75% water) were sequentially addedthereto, followed by heating to reflux for 100 minutes under closeirradiation with a 300 W lamp. The reaction mixture was left to becooled, then the insoluble material was collected by filtration, and theobtained filtrate was washed with water, followed by extraction with anappropriate amount of CHCl₃. The organic layer was sequentially washedwith a 5% (W/W) aqueous sodium thiosulfate solution (600 g) and brine,and dried over MgSO₄, and then the solvent was evaporated. To theobtained residue was added THF (300 mL), followed by sequential additiondropwise of diethyl phosphite (18.9 mL) and a Hunig's base (25.4 mL) atabout 0° C. under an argon atmosphere. Thereafter, the temperature wasslowly elevated, and the mixture was stirred at room temperature forabout 2 hours. An appropriate amount of ice water was poured into thereaction mixture, followed by extraction with ethyl acetate severaltimes. The organic layer was sequentially washed with 0.3 M hydrochloricacid (1 L) and brine, and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) toprepare ethyl [2-(bromomethyl)-1,3-thiazol-4-yl]carboxylate (26.82 g).

Preparation Example 23

Ethyl 2-methyl-1,3-thiazole-4-carboxylate (10 g) was added toacetonitrile (100 mL), and subsequently, NBS (11.4 g) was added thereto,followed by stirring for 3 hours under heating to reflux. To thereaction mixture was added NBS (5.0 g), followed by stirring for 2 hoursunder refluxing, and then NBS (5.0 g) was further added thereto,followed by stirring for about 12 hours under the same condition. Anappropriate amount of a saturated aqueous sodium hydrogen carbonatesolution was slowly poured into the reaction mixture under cooling,followed by extraction with ethyl acetate. The organic layer was washedwith brine and dried over MgSO₄, and then the solvent was evaporated.The obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:2) to prepare ethyl5-bromo-2-methyl-1,3-thiazole-4-carboxylate (8.86 g).

Preparation Example 24

Ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (6.84 g) was added tocarbon tetrachloride (114 mL), and subsequently, NBS (5.35 g) and AIBN(2.25 g) were added thereto, followed by stirring at about 90° C. for 2hours, and then NBS (5.0 g) and AIBN (0.9 g) were added thereto,followed by heating to reflux for additional 1 hour. The reactionmixture was left to be cooled, then the insoluble material was collectedby filtration, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:2) to prepare ethyl5-bromo-2-(bromomethyl)-1,3-thiazole-4-carboxylate (5.55 g).

Preparation Example 25

Ethyl 2-methyl-1,3-thiazole-4-carboxylate (10 g) was added to DMF (100mL) under ice-cooling, and subsequently, trichloroisocyanuric acid (13.6g) was slowly added thereto, followed by stirring at room temperatureovernight. Thereafter, an equivalent amount of trichloroisocyanuric acidwas added thereto several times in divided portions, followed bystirring at room temperature for one day. The insoluble material in thereaction mixture was collected by filtration through Celite, and to thefiltrate was added ice water including an appropriate amount of a 1 Maqueous sodium hydroxide solution, followed by extraction with ethylacetate. The organic layer was washed with brine and dried over MgSO₄,and then the solvent was evaporated. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) toprepare ethyl 5-chloro-2-methyl-1,3-thiazole-4-carboxylate (6.7 g).

Preparation Example 26

3-Phenylpropan-1-amine (11.33 g) and potassium carbonate (11.58 g) wereadded to acetonitrile (300 mL), and MeOH and a solution of ethyl2-(bromomethyl)-1,3-thiazole-4-carboxylate (11.64 g) in acetonitrile (30mL) in an ice bath were slowly added dropwise thereto, followed bystirring at room temperature for about 1 hour. To the reaction mixturewas added an appropriate amount of ice water, followed by extractionwith ethyl acetate several times. The organic layer was washed withbrine and dried over MgSO₄, and then the solvent was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=3:1 to 5:1) to prepare ethyl2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate (13.17 g).

Preparation Example 27

Ethyl 5-(chloromethyl)isoxazole-3-carboxylate (1.0 g) was added toacetonitrile (20 mL), and subsequently, 3-phenylpropyl amine (1.5 mL)and potassium carbonate (1.46 g) were added thereto under ice-cooling,followed by stirring at 60° C. overnight. The reaction mixture was leftto be cooled, and then the solvent was evaporated under reducedpressure. To the obtained residue was added an appropriate amount ofethyl acetate, followed by stirring for a while. Thereafter, theinsoluble material was collected by filtration and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:1) toprepare ethyl 5-{[(3-phenylpropyl)amino]methyl}isoxazole-3-carboxylate(0.94 g).

Preparation Example 28

Ethyl 2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate (1 g)was added to THF (12 mL), and subsequently, di-tert-butyl dicarbonate(0.72 g) was slowly added thereto under ice-cooling, followed bystirring at room temperature for about 2 hours. The reaction mixture wasconcentrated under reduced pressure, and the obtained colorless oilysubstance was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to prepare ethyl2-{[(tert-butoxycarbonyl)(3-phenylpropyl)aminomethyl]methyl}-1,3-thiazole-4-carboxylate(1.31 g).

Preparation Example 29

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate(1.24 g) was added to methylene chloride (25 mL), and subsequently,tert-butyldimethylchlorosilane (0.4 g), triethylamine (0.34 mL), andDMAP (0.15 g) were sequentially added thereto, followed by stirring forabout 3 hours. To the reaction mixture was added CHCl₃, followed bysequentially washing with an appropriate amount of an aqueous ammoniumchloride solution and brine. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:1) toprepare ethyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(1.46 g).

Preparation Example 30

tert-Butyl[(4-{[(dimethylamino)sulfonyl]carbamoyl}-1,3-thiazol-2-yl)methyl](3-phenylpropyl)carbamate(0.87 g) was added to ethyl acetate (1 mL), and subsequently, a 4 Mhydrochloric acid/ethyl acetate solution (4 mL) was poured thereinto,followed by stirring at room temperature for about 12 hours under asealed argon gas atmosphere. After diluting and subsequently washing thereaction mixture with an appropriate amount of diethyl ether, a whiteprecipitate was collected by filtration/dried to prepareN-[(dimethylamino)sulfonyl]-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamidehydrochloride (0.74 g) as a white solid.

Preparation Example 31

5-Formyl-furan-2-carboxylic acid (3.5 g) was added to DMF (35 mL), andsubsequently, potassium carbonate and ethyl iodide (2.22 mL) were addedthereto under ice-cooling, followed by stirring at room temperatureovernight. To the reaction mixture was added an appropriate amount ofice water, followed by extraction with ethyl acetate several times. Theorganic layer was dried over Na₂SO₄, and the solvent was evaporated toprepare ethyl 5-formyl-furan-2-carboxylate (2.56 g).

Subsequently, ethyl 5-{[(3-phenylpropyl)amino]methyl}-2-furoate (0.64 g)was prepared from ethyl 5-formyl-furan-2-carboxylate (500 mg) and3-phenylpropylamine (0.85 mL) in the same manner as in PreparationExample 52.

Next, ethyl5-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-2-furoate(454 mg) was prepared from ethyl5-{[(3-phenylpropyl)amino]methyl}-2-furoate (330 mg) in the same manneras in Preparation Example 56.

Preparation Example 32

tert-Butyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(0.49 g) was added to THF (6 mL), and subsequently, a 1 M TBAF/THFsolution (3 mL) was added dropwise thereto, followed by stirring at roomtemperature for about 5 hours. The reaction mixture was concentrated,and to the obtained residue was added a cooled mixed aqueous solution of1 M hydrochloric acid/saturated ammonium chloride (1:1), followed byextraction with an appropriate amount of ethyl acetate twice. Theorganic layer was washed with brine and dried over MgSO₄, and then thesolvent was evaporated. The obtained pale brown oily substance waspurified by silica gel column chromatography (ethyl acetate:hexane=3:2)to prepare tert-butyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate(0.33 g).

Preparation Example 33

Ethyl 2-(diethoxymethyl)-5-methyl-1,3-thiazole-4-carboxylate (12.1 g)was added to acetone (300 mL), and subsequently, 1 M hydrochloric acid(150 mL) was added thereto, followed by stirring at 55° C. for about 5hours. The reaction mixture was concentrated, neutralized by theaddition of an appropriate amount of a saturated aqueous sodium hydrogencarbonate solution, and then extracted with ethyl acetate several times.The organic layer was dried over MgSO₄, and the solvent was evaporatedunder reduced pressure to prepare ethyl2-formyl-5-methyl-1,3-thiazole-4-carboxylate (8.25 g).

Preparation Example 34

2-{[(tert-Butoxycarbonyl)(3-phenylpropyl)aminomethyl]methyl}-1,3-thiazole-4-carboxylicacid (0.8 g) was added to anhydrous THF (30 mL), and subsequently, CDI(0.52 g) was added thereto, followed by stirring at about 60° C. for 1hour under an argon atmosphere. The reaction mixture was ice-cooled, andN,N-dimethylsulfamide (0.53 g) and DBU (0.42 g) were sequentially addedthereto, followed by stirring at room temperature for about 6 hours. Tothe reaction mixture was added an appropriate amount of 1 M hydrochloricacid and ice water, followed by extraction with ethyl acetate severaltimes. The organic layer was washed with brine and dried over MgSO₄, andthen the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography(CHCl₃:MeOH=200:1) to prepare tert-butyl[(4-{[(dimethylamino)sulfonyl]carbamoyl}-1,3-thiazol-2-yl)methyl](3-phenylpropyl)carbamate(0.9 g).

Preparation Example 35

Benzyl [(3-hydroxypyrrolidin-1-yl)sulfonyl]carbamate (2.55 g) was addedto MeOH, and subsequently, 10% palladium carbon (657 mg, 55% wet),followed by stirring at a normal temperature/a normal pressure for about3 hours under a hydrogen atmosphere. The catalyst was collected byfiltration through Celite, and the filtrate was concentrated underreduced pressure to obtain 3-hydroxypyrrolidin-1-sulfonamide (1.4 g) asa colorless oily substance.

Preparation Example 36

2,2-diethoxyethanethioamide (9.21 g), calcium carbonate (3.39 g), and anappropriate amount of powder Molecular Sieves (4 Angstrom, about 2 timesa medicinal spoon) were added to EtOH (220 mL), and subsequently, ethyl3-bromo-2-oxobutanoate (13.1 g) prepared by the method by Plouvier, etal. (Heterocycles, 1991 32, 693.) was added dropwise thereto over about5 minutes, followed by stirring at room temperature for about 30minutes. Thereafter, the mixture was further warmed to 55° C. for about6 hours. The reaction mixture was left to be cooled, then the insolublematerial was collected by filtration, and the filtrate was concentratedunder reduced pressure. To the obtained residue was added an appropriateamount of water, followed by extraction with ethyl acetate twice. Theorganic layer was washed with brine and dried over MgSO₄, and then thesolvent was evaporated. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=7:3) to prepare ethyl2-(diethoxymethyl)-5-methyl-1,3-thiazole-4-carboxylate (12.1 g).

Preparation Example 37

Methyl 4-formyl-3,5-dimethoxybenzoate (3.01 g) was added to a MeOH/THF(1:1) solution (30 mL), and subsequently, 0.3 g of sodium borohydridewas added thereto under ice-cooling, followed by stirring at the sametemperature for about 30 minutes. The reaction mixture was concentrated,and 0.5 M hydrochloric acid (24 mL) was poured into the obtainedresidue, followed by stirring at room temperature for about 30 minutes.The resulting insoluble material was collected by filtration to preparemethyl 3,5-dimethoxy-4-(hydroxymethyl)benzoate (2.78 g) as a whitesolid.

Preparation Example 38

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-formyl-1,3-thiazole-4-carboxylate(1.57 g) was added to methylene chloride (25 mL), and subsequently,sodium triacetoxyborohydride (1.96 g) was added thereto in an ice bath,followed by stirring at room temperature for about 14 hours. Thereafter,sodium triacetoxyborohydride (1.5 g) was further added thereto, followedby stirring at room temperature for 5 hours. To the reaction mixture wasadded an appropriate amount of CHCl₃, and an appropriate amount of anaqueous sodium hydrogen carbonate solution was added thereto, followedby stirring for a while. The reaction mixture was subjected to liquidseparation, subsequently, the organic layer was washed with brine anddried over MgSO₄, and then the solvent was evaporated. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane=3:1) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate(1.25 g).

Preparation Example 39

3-Phenylpropan-1-amine (1.3 g) was added to methylene chloride (30 mL),and subsequently, ethyl 2-formyl-5-methyl-1,3-thiazole-4-carboxylate(1.2 g) and acetic acid (1.5 mL) were sequentially added thereto,followed by stirring at room temperature for about 20 minutes.Thereafter, sodium triacetoxyborohydride (2.69 g) was added theretounder ice-cooling, followed by stirring at room temperature for about 1hour. To the reaction mixture was added CHCl₃, and an appropriate amountof a saturated aqueous sodium hydrogen carbonate solution was furtheradded thereto, followed by stirring and then performingliquid-separation. The organic layer was dried over MgSO₄, and then thesolvent was evaporated under reduced pressure. The obtained yellow oilysubstance was purified by silica gel column chromatography(CHCl₃:MeOH=250:1) to prepare ethyl5-methyl-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(1.56 g).

Preparation Example 40

Under an argon atmosphere, chlorosulfonylisocyanate (0.15 mL) was addedto methylene chloride (9.5 mL), followed by cooling in an MeOH/ice bath.Subsequently, tert-butanol (0.18 mL) was added dropwise thereto,followed by stirring for about 30 minutes under cooling. To the reactionmixture were slowly sequentially added triethylamine (0.61 mL) and2-fluoro-N-methyl ethanamine hydrochloride (197 mg), followed bystirring for 30 minutes under cooling, warming to room temperature, andthen further stirring overnight. The solvent was evaporated underreduced pressure, and to the obtained residue was added an appropriateamount of purified water, followed by acidification with 1 Mhydrochloric acid, and then extraction with ethyl acetate. The organiclayer was washed with brine and dried over MgSO₄, and then the solventwas evaporated under reduced pressure to prepare tert-butyl{[(2-fluoroethyl)(methyl)amino]sulfonyl}carbamate (412 mg) as acolorless oily substance.

Preparation Example 41

Under an argon atmosphere, chlorosulfonylisocyanate (1 mL) was added tomethylene chloride (67 mL), and the mixture was cooled in an MeOH/icebath. Subsequently, benzyl alcohol (1.26 mL) was added dropwise thereto,followed by stirring for about 30 minutes under cooling. To the reactionmixture were slowly sequentially added triethylamine (2.42 mL) and3-hydroxypyrrolidine (1.22 mL), followed by stirring for 30 minutesunder cooling, then warming to room temperature, and further stirringovernight. The solvent was evaporated under reduced pressure, and to theobtained residue was added an appropriate amount of purified water,followed by acidification with 1 M hydrochloric acid, and thenextraction with ethyl acetate. The organic layer was washed with brineand dried over MgSO₄, and then the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1 to 2:1) to prepare benzyl[(3-hydroxypyrrolidin-1-yl)sulfonyl]carbamate (2.55 g) as a white solid.

Preparation Example 42

Ethyl 2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate (3.2g) and triethylamine (1.61 mL) were added to acetonitrile (70 mL), andthe mixture was sufficiently cooled in an MeOH/ice bath. Subsequently,3,5-dimethoxy-4-methylbenzoyl chloride (2.48 g) was slowly addedthereto, followed by stirring at room temperature for 1 hour. Thesolvent was evaporated, and to the obtained residue was added anappropriate amount of a saturated aqueous sodium hydrogen carbonatesolution, followed by stirring for 2 to 3 minutes and then extractionwith ethyl acetate several times. The organic layer was sequentiallywashed with 1 M hydrochloric acid/a saturated aqueous ammonium chloridesolution and brine, and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure. The obtained colorless oily substancewas purified by silica gel column chromatography (ethylacetate:hexane=1:1) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(4.93 g).

Preparation Example 43

Anhydrous acetic acid (0.5 mL) was added to pyridine (2 mL), andsubsequently tert-butyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-(hydroxymethyl)-1,3-thiazole-4-carboxylate(140 mg) was added thereto under ice-cooling, followed by stirring atroom temperature for about 1.5 hours. To the reaction mixture was addedan appropriate amount of toluene, followed by concentration underreduced pressure. This procedure was repeated twice, and to the obtainedresidue was added 0.5 M hydrochloric acid that had been cooled, followedby extraction with ethyl acetate several times. The organic layer waswashed with brine and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure to prepare tert-butyl5-(acetoxymethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(150 mg).

Preparation Example 44

Ethyl2-({[(2,4-dimethoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxylatewas prepared from ethyl5-methyl-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate inthe same manner as the method of Example 1 as described later.

Preparation Example 45

3,5-Dimethoxy-4-bromobenzoic acid (10 g) was added to DMF (100 mL), andsubsequently, CDI (9.32 g) was slowly added thereto at room temperature,followed by stirring at about 40° C. for 1 hour. Further, to thereaction mixture were sequentially added dropwise tert-butanol (7.4 mL)and DBU (6.3 mL), followed by stirring at about 40° C. for about 3 days.An appropriate amount of ethyl acetate was poured into the reactionmixture, followed by sequentially washing with dilluted hydrochloricacid, an aqueous sodium hydrogen carbonate solution, and brine. Theorganic layer was dried over MgSO₄, and then the solvent was evaporatedunder reduced pressure to prepare tert-butyl4-bromo-3,5-dimethoxybenzoate (11 g) as a white solid.

tert-Butyl 4-bromo-3,5-dimethoxybenzoate (2.22 g) was added to anhydrousTI-IF (50 mL), followed by cooling to around −78° C. under an argonatmosphere, and to the mixture was added dropwise a 2.73 M n-butyllithium/n-hexane solution (3.1 mL), followed by stirring for about 30minutes under cooling (about −78° C.). To the reaction mixture was addeddropwise DMF (1.1 mL), followed by stirring at the same temperature forabout 10 minutes, and then a saturated aqueous ammonium chloridesolution was poured thereinto, followed by extraction with anappropriate amount of ethyl acetate twice. The organic layer was washedwith brine and dried over MgSO₄, and then the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=3:2) to prepare tert-butyl4-formyl-3,5-dimethoxybenzoate (1.44 g) as a white powder.

Preparation Example 46

Ethyl 3,5-dimethoxy-4-vinylbenzoate (1.05 g) and 10% palladium/carbon(100 mg) were added to ethyl acetate (20 mL), followed by stirring at anormal temperature/a normal pressure for about 12 hours under a hydrogenatmosphere. The catalyst was collected by filtration through Celite andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:1) to prepare 3,5-dimethoxy-4-ethylbenzoate (902 mg).

Ethyl 3,5-dimethoxy-4-ethylbenzoate (0.35 g) was added to an EtOH/THF(1:2)(6 mL) solution, and subsequently, a 1 M aqueous sodium hydroxidesolution (3.7 mL) was added dropwise thereto, followed by stirring atroom temperature for about 15 hours. The reaction mixture wasconcentrated under reduced pressure to a half amount, and ice water(about 20 to 30 g) including 1 M hydrochloric acid (6 mL) was addedthereto, followed by extraction with CHCl₃ several times. The organiclayer was washed with water and dried over MgSO₄, and then the solventwas evaporated under reduced pressure to prepare3,5-dimethoxy-4-ethylbenzoic acid (0.28 g).

Preparation Example 47

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-vinyl-1,3-thiazole-4-carboxylate(235 mg) and 10% palladium/carbon (48 mg) were added to EtOH/THF (1:1)(8 mL), followed by stirring at a normal temperature/a normal pressurefor 4 hours under a hydrogen atmosphere. The reaction mixture wasfiltered through Celite, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=2:3) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-ethyl-1,3-thiazole-4-carboxylate(198 mg).

Subsequently,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-ethyl-1,3-thiazole-4-carboxylicacid (110 mg) was prepared from ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-ethyl-1,3-thiazole-4-carboxylate(118 mg) in the same manner as the method of Preparation Example 5.

Preparation Example 48

Ethyl (2,4-dimethoxybenzoyl)formate (0.78 g) andbis(2-methoxyethyl)aminosulfur-trifluoride (1.8 g) were added to anappropriate amount of dichloroethane, followed by stirring at 60° C.overnight. To the reaction mixture were addedbis(2-methoxyethyl)aminosulfur-trifluoride (1.8 g), followed by stirringat 60° C. overnight. The reaction mixture was neutralized by theaddition of an appropriate amount of a saturated aqueous sodium hydrogencarbonate solution under ice-cooling, followed by extraction with CHCl₃.The organic layer was dried over Na₂SO₄, and then the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (ethyl acetate:hexane=1:2) to prepareethyl (2,4-dimethoxyphenyl)(difluoro)acetate (852 mg).

Subsequently, (2,4-dimethoxyphenyl)(difluoro)acetic acid (214 mg) wasprepared from ethyl (2,4-dimethoxyphenyl)(difluoro)acetate (0.24 g) inthe same manner as the method of Preparation Example 3.

Preparation Example 49

2-Fluoro-4-methoxybenzaldehyde (1.0 g), triethylamine (0.2 mL), andtrimethylsilylcyanide (0.9 mL) were added to methylene chloride (10 mL),followed by stirring at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure, and to the obtainedresidue were added EtOH (12 mL) and chlorotrimethylsilane (12 mL),followed by stirring at room temperature overnight. The reaction mixturewas left to be cooled, and then the solvent was evaporated.Dichloroethane (20 mL), EtOH (10 mL), and a saturated aqueous sodiumhydrogen carbonate solution (20 mL) were poured into the obtainedresidue, followed by severely stirring at room temperature for about 3hours. The reaction mixture was extracted with an appropriate amount ofCHCl₃, the organic layer was dried over MgSO₄, and then the solvent wasevaporated under reduced pressure to prepare ethyl(2-fluoro-4-methoxyphenyl)(hydroxy)acetate (0.67 g).

Subsequently, (2-fluoro-4-methoxyphenyl)(hydroxy)acetic acid (0.35 g)was prepared from ethyl (2-fluoro-4-methoxyphenyl)(hydroxy)acetate (0.67g) in the same manner as the method of Preparation Example 3.

Preparation Example 50

Under ice-cooling, a Burgess reagent(3,3,3-triethyl-1-(methoxycarbonyl)diazathia-3-ium-1-iodo-2,2-dioxide)(2.0 g) and concentrated aqueous ammonia (to 30%) (1.6 mL) were added totoluene (20 mL), followed by stirring at room temperature for 3 hours.The mixture was neutralized with 0.5 M hydrochloric acid and thenextracted with an appropriate amount of ethyl acetate. The organic layerwas washed with brine and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure to prepare methyl(aminosulfonyl)carbamate (650 mg).

Subsequently, methyl (aminosulfonyl)carbamate (160 mg), benzyl alcohol(0.14 mL), and triphenylphosphine (354 mg) were added to THF (4.9 mL),and subsequently, a 2.2 M DEAD/toluene solution (0.61 mL) was addedthereto under ice-cooling, followed by stirring at room temperature for3 hours. The solvent was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1 to 2:1) to prepare methyl(aminosulfonyl)benzylcarbamate (214 mg).

Preparation Example 51

Under ice-cooling, to DMF (31 mL) was slowly added dropwise phosphorousoxychloride (4.47 mL), followed by stirring at the same temperature forabout 15 minutes. To the reaction mixture was added methyl1H-pyrrole-2-carboxylate (5.0 g), followed by slowly warming to 60° C.and stirring for about 5 hours. The reaction mixture was neutralized bythe addition of a 8 M aqueous sodium hydroxide solution underice-cooling, followed by extraction with ethyl acetate several times.The organic layer was washed with brine and dried over MgSO₄, and thenthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (ethylacetate:hexane=1:1) to prepare methyl 5-formyl-1H-pyrrole-2-carboxylate(2.53 g).

Subsequently, methyl5-{[(3-phenylpropyl)amino]methyl}-1H-pyrrole-2-carboxylate (1.28 g) wasprepared from methyl 5-formyl-1H-pyrrole-2-carboxylate (1.0 g) in thesame manner as the method of Preparation Example 52.

Preparation Example 52

Ethyl 3,5-dimethoxy-4-formylbenzoate (0.6 g) was added to a MeOH/THF(1:1) (30 mL) solution, and sodium borohydride (0.19 g) was addedthereto under ice-cooling, followed by stirring at room temperature for3 hours. The solvent was evaporated, and the obtained residue wasdissolved in an appropriate amount of ethyl acetate, followed bysequentially washing with appropriate amounts of 1 M hydrochloric acid,an aqueous sodium hydrogen carbonate solution, and brine, and performingliquid-separation. The organic layer was dried over MgSO₄, and then thesolvent was evaporated to prepare ethyl3,5-dimethoxy-4-(hydroxymethyl)benzoate (0.55 g) as a white solid.

Subsequently, ethyl 3,5-dimethoxy-4-(hydroxymethyl)benzoate (300 mg) wasadded to DMF (3 mL), and sodium hydride (60 mg) and methyl iodide (0.16mL) were sequentially added thereto, followed by stirring at roomtemperature for about 6 hours. To the reaction mixture was added anappropriate amount of ethyl acetate, and the insoluble material wascollected by filtration and then washed with purified water and brine.The organic layer was dried over Na₂SO₄, and then the solvent wasevaporated to prepare ethyl 3,5-dimethoxy-4-(methoxymethyl)benzoate (300mg).

Furthermore, ethyl 3,5-dimethoxy-4-(methoxymethyl)benzoate (300 mg) wasadded to an EtOH/THF (1:2) solution (7.5 mL), and subsequently, a 1 Maqueous sodium hydroxide solution (2.3 mL) was added dropwise thereto,followed by stirring at room temperature for about 15 hours. The solventwas evaporated under reduced pressure to about a half amount, thereaction mixture was concentrated, and ice water (about 20 to 30 g)including 1 M hydrochloric acid (6 mL) was poured into the obtainedresidue, followed by extraction with CHCl₃ several times. The organiclayer was washed with and dried over Na₂SO₄, and then the solvent wasevaporated to prepare 3,5-dimethoxy-4-(methoxymethyl)benzoic acid (240mg).

Preparation Example 53

1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid (1.07 g) was added toEtOH (20 mL), and concentrated sulfuric acid (0.1 mL) was added dropwisethereto, followed by stirring at 70° C. for 2 days. The solvent wasevaporated under reduced pressure, and to the obtained residue was addeda saturated aqueous sodium hydrogen carbonate solution, followed byextraction with an appropriate amount of ethyl acetate. The organiclayer was washed with brine and dried over Na₂SO₄, and then the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate-2:1) toprepare ethyl 1-(4-hydroxyphenyl)cyclopropanecarboxylate (1.15 g) as apale yellow solid.

Subsequently, ethyl 1-(4-hydroxyphenyl)cyclopropanecarboxylate (200 mg),triphenylphosphine (382 mg), and 2-fluoroethanol (93 mg) were added toTHF, and subsequently, DBAD (335 mg) was added thereto underice-cooling, followed by stirring at room temperature overnight. Thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1) to prepare ethyl1-[4-(2-fluoroethoxy)phenyl]cyclopropanecarboxylate (190 mg) as acolorless oily substance.

Furthermore, ethyl 1-[4-(2-fluoroethoxy)phenyl]cyclopropanecarboxylate(190 mg) was added to an EtOH/THF (1:1) solution (10 mL), andsubsequently, a 1 M aqueous sodium hydroxide solution (2 mL) was addeddropwise thereto, followed by stirring at room temperature overnight.The reaction mixture was concentrated under reduced pressure andneutralized by the addition of purified water and 1 M hydrochloric acid,and then resulting insoluble material was collected by filtration toprepare 1-[4-(2-fluoroethoxy)phenyl]cyclopropanecarboxylic acid (152 mg)as a white solid.

Preparation Example 54

The following products were prepared with a partial modification of themethod of Johnson, et al. (Tetrahedron Lett., 2004 45, 8483-8487.).

N-Benzylmethane sulfonamide (2.0 g) was added to THF (40 mL), andsubsequently, a 1.66 M solution of n-butyl lithium in n-hexane (13.1 mL)was added dropwise thereto under cooling at −78° C., followed bystirring for 5 minutes and then warming to 0° C. To the reaction mixturewas slowly added dropwise a mixture prepared by adding acetaldehyde (2.4mL) to THF (20 mL), followed by stirring for 2 hours while warming toroom temperature. To the reaction mixture was added an aqueous ammoniumchloride solution, followed by extraction with CHCl₃, the aqueous layerwas separated with a phase separator, and the solvent of the organiclayer was evaporated. The obtained residue was purified by silica gelcolumn chromatography (CHCl₃:MeOH=20:1) to prepareN-benzyl-2-hydroxypropane-1-sulfonamide (1.94 g) as a white solid.

Subsequently, N-benzyl-2-hydroxypropane-1-sulfonamide (1.94 g), DMAP(0.52 g), triethylamine (1.77 mL), and tert-butyldimethylchlorosilane(1.91 g) were added to methylene chloride (50 mL), followed by stirringat room temperature overnight. To the reaction mixture was added anaqueous ammonium chloride solution, followed by extraction with ethylacetate. The organic layer was washed with brine and dried by theaddition of MgSO₄, and the solvent was evaporated. The obtained residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1) to prepare N-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}propane-1-sulfonamide (1.84 g).

Furthermore, N-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}propane-1-sulfonamide (1.8 g) and 10% palladiumhydroxide (0.5 g) were added to ethyl acetate (30 mL), followed bystirring at room temperature for 3 hours under a hydrogen atmosphere.The reaction mixture was filtered through Celite and the solvent wasevaporated. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=10:1) to prepare 2-{[tert-butyl(dimethyl)silyl]oxy}propane-1-sulfonamide (1.04 g) as a white solid.

Preparation Example 93

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (500 mg) and CDI (268 mg) were added to THF (30 mL), followed bystirring at 60° C. for 1 hour. To the reaction mixture were added3-{[tert-butyl (dimethyl)silyl]oxy}pyrrolidin-1-sulfonamide (370 mg) andDBU (251 mg) under ice-cooling, followed by stirring at room temperatureovernight. The solvent was evaporated under reduced pressure andneutralized by the addition of an appropriate amount of purified waterand 1 M hydrochloric acid, followed by extraction with CHCl₃ severaltimes. The organic layer was washed with brine and then dried overMgSO₄, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:2) to prepare N-[(3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(580 mg).

Preparation Example 106

To a mixture of ethyl 2-formyl-1,3-thiazole-4-carboxylate (7.4 mg),2-phenethylamine (4.8 mg), acetic acid (50 μL), and DMF (0.45 mL) wasadded MP-Triacetoxyborohydride (Biotage) (75 mg), followed by stirringat room temperature overnight. To the reaction mixture was addedPS-Benzaldehyde (Biotage) (50 mg), followed by stirring at roomtemperature for 4 hours, and the insoluble material was collected byfiltration. The filtrate was purified by solid-phase extraction usingBondElut SCX (Varian) (eluent, concentrated aqueous ammonia:MeOH=1:9).To the obtained crude purified product was added a mixture of3,5-dimethoxybenzoic acid (7.3 mg), HOBT (5.4 mg), and DMF (1.0 mL), andPS-Carbodiimide (Biotage) (100 mg) was added thereto, followed bystirring at room temperature overnight. To the reaction mixture wereadded MP-Carbonate (Biotage) (50 mg) and PS-Isocyanate (Biotage) (50mg), followed by stirring at room temperature for 4 hours, and theinsoluble material was collected by filtration. The filtrate wasconcentrated under reduced pressure, and to the obtained residue weresequentially added EtOH (0.4 mL), THF (0.4 mL), and 1 M aqueous sodiumhydroxide solution (0.4 mL), followed by stirring at room temperatureovernight. To the reaction mixture was added 1 M hydrochloric acid (0.4mL), and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by preparative liquid chromatography/massspectroscopy device (MeOH/0.1% aqueous formic acid solution) to prepare2-{[(3,5-dimethoxybenzoyl)(2-phenylethyl)amino]methyl}-1,3-thiazole-4-carboxylic acid (6.4 mg).

Preparation Example 216

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-vinyl-1,3-thiazole-4-carboxylate(235 mg) and 10% palladium/carbon (48 mg) were added to an EtOH/THF(1:1) solution (7.8 mL), followed by stirring at a normal temperature/anormal pressure for 4 hours under a hydrogen atmosphere. The catalystwas filtered through Celite, the filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=2:3) to prepare ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-ethyl-1,3-thiazole-4-carboxylate(198 mg) as a colorless oily substance.

Preparation Example 219

Ethyl2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (1.5 g), WSCD HCl (0.76 g), HOBT (0.54 g), and ammonium chloride(0.53 g) were added to DMF (50 mL), and subsequently, triethylamine(1.38 mL) was added dropwise thereto, followed by stirring at roomtemperature overnight. To the reaction mixture was added a saturatedaqueous sodium hydrogen carbonate solution, followed by extraction withethyl acetate. The organic layer was washed with brine and dried overMgSO₄, and then the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃:MeOH=10:1) to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(1.35 g).

Preparation Example 400

To a solution containing tert-butyl1-(4-bromophenyl)cyclopropanecarboxylate (2.0 g) in THF (50 mL) wasadded a 2.6 M n-BuLi solution in hexane (2.8 mL) at −78° C., followed bystirring for about 2 minutes, and DMF (0.7 mL) was added thereto,followed by warming to −50° C. and stirring for about 1 hour. Thereaction mixture was returned to room temperature, an appropriate amountof a saturated aqueous ammonium chloride solution was added thereto,followed by extraction with CH₃Cl, and the organic layer was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to prepare tert-butyl1-(4-formylphenyl)cyclopropanecarboxylate (1.41 g) as a colorless oilysubstance.

Preparation Example 401

tert-Butyl 1-(4-formylphenyl)cyclopropanecarboxylate (1.4 g) was addedto EtOH (2 mL), and sodium borohydride (0.25 g) was added thereto at 0°C., followed by stirring at room temperature for 1 hour. To the reactionmixture was added an appropriate amount of purified water, followed byextraction with CHCl₃, and the solvent was evaporated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=2:1)to prepare tert-butyl 1-[4-(hydroxymethyl)phenyl]cyclopropanecarboxylate(1.39 g) as a colorless oily substance.

Preparation Example 402

tert-Butyl 1-[4-(hydroxymethyl)phenyl]cyclopropanecarboxylate (700 mg)was added to DMF (12 mL), and 55% sodium hydride (250 mg) was addedthereto under ice-cooling, followed by stirring for 10 minutes.Iodomethane (0.3 mL) was added thereto, followed by returning to roomtemperature and stirring at room temperature for 1 hour. To the reactionmixture was added an appropriate amount of a saturated aqueous ammoniumchloride solution, followed by extraction with CHCl₃, and the solventwas evaporated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to prepare tert-butyl1-[4-(methoxymethyl)phenyl]cyclopropanecarboxylate (580 mg) as acolorless oily substance.

Preparation Example 403

[4-(Methylsulfanyl)phenyl]acetonitrile (2.5 g) andN-benzyl-N,N,N-triethylammonium chloride (0.38 g) was added tobromochloroethane (2.8 mL), and a 50% aqueous sodium hydroxide solution(15 mL) was slowly added thereto under ice-cooling. The reaction mixturewas stirred at 40° C. for 18 hours. To the reaction mixture was added anappropriate amount of ice water, followed by extraction with toluene,and the organic layer was washed with brine, dried over Na₂SO₄, and thenevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to prepare1-[4-(methylsulfanyl)phenyl]cyclopropanecarbonitrile (2.82 g) as acolorless oily substance.

Next, 1-[4-(methylsulfanyl)phenyl]cyclopropanecarbonitrile (2.82 g) andpotassium hydroxide (2.4 g) were added to a mixed solution of purifiedwater (15 mL) and ethylene glycol (15 mL), followed by stirring at 140°C. for 4 hours. The reaction mixture was poured into a mixed solution ofice water (100 mL) and 6 M hydrochloric acid (50 mL), and theprecipitated solid was collected by filtration and dried under reducedpressure to prepare 1-[4-(methylsulfanyl)phenyl]cyclopropanecarboxylicacid (1.09 g) as a white solid.

Preparation Example 405

2-Fluoro-4-hydroxybenzaldehyde (5.0 g), triphenylphosphine (14 g), and2-fluoroethanol (3.43 g) were added to THF (150 mL), and diisopropyl(E)-diazene-1,2-dicarboxylate (10.82 g) was added thereto underice-cooling, followed by stirring at room temperature for one week. Thereaction mixture was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography (hexane to hexane:ethylacetate=3:1) to prepare 2-fluoro-4-(2-fluoroethoxy)benzaldehyde (4.9 g)as a white solid.

Preparation Example 408

2-Fluoro-4-(2-fluoroethoxy)benzaldehyde (4.9 g), triethylamine (0.73 mL)and trimethylsilanecarbonitrile (4.0 mL) were sequentially added tomethylene chloride (50 mL), followed by stirring at room temperatureovernight. The reaction mixture was evaporated under reduced pressure,and to the residue were added EtOH (50 mL) and chlorotrimethylsilane(9.8 mL), followed by stirring at 50° C. for 5 hours. Further, anappropriate amount of saturated sodium bicarbonate water was addedthereto, followed by stirring at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure, and the residue wasextract with an appropriate amount of ethyl acetate, washed with brine,and then dried over Na₂SO₄. The residue was purified by silica gelcolumn chromatography (hexane to hexane:ethyl acetate=1:1) to prepareethyl [2-fluoro-4-(2-fluoroethoxy)phenyl](hydroxy)acetate (4.0 g) as acolorless solid.

Preparation Example 411

Ethyl [2-fluoro-4-(2-fluoroethoxy)phenyl](hydroxy)acetate (4.0 g),[2-(chloromethoxy)ethyl](trimethyl)silane (0.4 mL), a Hunig's base (0.5mL), and tetra-n-butylammonium iodide (0.78 g) were sequentially addedto methylene chloride (5 mL), followed by stirring at room temperaturefor 5 hours, and then [2-(chloromethoxy)ethyl](trimethyl) silane (0.4mL), a Hunig's base (0.5 mL), and tetra-n-butylammonium iodide (0.78 g)were added thereto, followed by further stirring for 3 hours. Thereaction mixture was evaporated under reduced pressure, and anappropriate amount of purified water was added thereto. The mixture wasextracted with ethyl acetate, then washed with brine, and dried overNa₂SO₄. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (hexane tohexane:ethyl acetate=5:1) to prepare ethyl[2-fluoro-4-(2-fluoroethoxy)phenyl]{[2-(trimethylsilyl)ethoxy]methoxy}acetate(0.56 g) as a colorless oily substance.

Preparation Example 420

2-Fluoro-4-hydroxybenzaldehyde (1.5 g), 1-iodopropane (1.26 mL), andpotassium carbonate (2.22 g) were sequentially added to acetonitrile (38mL), followed by stirring at 60° C. for 5 hours. To the reaction mixturewas added an appropriate amount of ethyl acetate, followed by stirringfor a while. Then, the insoluble material was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane to hexane:ethyl acetate=5:1) toprepare 2-fluoro-4-propoxybenzaldehyde (1.49 g) as a colorless oilysubstance.

Preparation Example 421

Ethyl5-methyl-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(0.8 g), a Hunig's base (0.15 mL), (4-ethoxy-2-fluorophenyl){[2-(trimethylsilyl)ethoxy]methoxy}acetic acid (0.95 g), and HATU (1.1g) were sequentially added to acetonitrile (53 mL), followed by stirringat room temperature for 3 hours. The reaction mixture was evaporatedunder reduced pressure, and to the residue were added an appropriateamount of purified water and 1 M hydrochloric acid, followed byextraction with CHCl₃. The organic layer was dried over Na₂SO₄ andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane to hexane:ethyl acetate=1:1) toprepare ethyl2-[4-(4-ethoxy-2-fluorophenyl)-10,10-dimethyl-3-oxo-2-(3-phenylpropyl)-5,7-dioxo-2-aza-10-silaneundec-1-yl]-5-methyl-1,3-thiazole-4-carboxylate(1.45 g) as a colorless oily substance.

Next, ethyl2-[4-(4-ethoxy-2-fluorophenyl)-10,10-dimethyl-3-oxo-2-(3-phenylpropyl)-5,7-dioxo-2-aza-10-silaneundec-1-yl]-5-methyl-1,3-thiazole-4-carboxylate(1.45 g) and a 1 M aqueous sodium hydroxide solution (5 mL) were addedto a THF/EtOH (1:1) solution (20 mL), followed by stirring at roomtemperature overnight. The reaction mixture was evaporated under reducedpressure, and the residue was neutralized by the addition of anappropriate amount of purified water and 1 M hydrochloric acid, and thenextracted with ethyl acetate. The organic layer was washed with brineand dried over Na₂SO₄, and then the solvent was evaporated under reducedpressure to prepare2-[4-(4-ethoxy-2-fluorophenyl)-10,10-dimethyl-3-oxo-2-(3-phenylpropyl)-5,7-dioxo-2-aza-10-silaneundec-1-yl]-5-methyl-1,3-thiazole-4-carboxylicacid (1.35 g).

Preparation Example 424

1-(4-Hydroxyphenyl)cyclopropanecarboxylate (4.5 g) and concentratedsulfuric acid (0.2 mL) were added to EtOH (60 mL), followed by stirringat 70° C. for 2 days. The reaction mixture was evaporated under reducedpressure, and to the residue was added an appropriate amount ofsaturated sodium bicarbonate water, followed by extraction with ethylacetate. The organic layer was washed with brine and dried over Na₂SO₄,and then the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane tohexane:ethyl acetate=2:1) to prepare ethyl1-(4-hydroxyphenyl)cyclopropanecarboxylate (5.0 g) as a pale yellowsolid.

Preparation Example 425

Ethyl 1-(4-hydroxyphenyl)cyclopropanecarboxylate (0.7 g), potassiumcarbonate (0.7 g), and iodomethane-d₂ were sequentially added to DMF (7mL), followed by stirring at room temperature overnight. To the reactionmixture was added an appropriate amount of ice water, followed byextraction with ethyl acetate. The organic layer was washed with brineand dried over Na₂SO₄, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane to hexane:ethyl acetate=5:1) to prepare ethyl1-{4-[(²H₂)methyloxy]phenyl}cyclopropanecarboxylate (0.705 g) as acolorless oily substance.

Preparation Example 429

A mixture of copper(II) trifluoromethanesulfonate (155 mg) and(4S,4′S)-2,2′-propane-2,2-diylbis(4-benzyl-4,5-dihydro-1,3-oxazole) (155mg) was dried for 30 minutes under reduced pressure, and then added tomethylene chloride (7 mL) under an argon air flow, followed by stirringat room temperature for 1 hour. To this mixture was added a solutioncontaining ethyl {4-[(²H₂)methyloxy]phenyl}(oxo)acetate (300 mg) inmethylene chloride (3 mL), followed by further stirring at roomtemperature for 30 minutes. To the reaction mixture was added diethyl2,6-dimethylpyridine-1,4-dihydropyridine-3,5-dicarboxylate (433 mg) inan ice bath, followed by stirring for 3 hours as it was and subsequentlystirring at room temperature overnight. To the reaction mixture wasadded an appropriate amount of purified water, followed by extractionwith CHCl₃, the organic layer was dried over Na₂SO₄, and then thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane to hexane:ethylacetate=1:1) to prepare ethyl(2R)-hydroxy{4-[(²H₂)methyloxy]phenyl}acetate (0.25 g) as a colorlessoily substance.

Preparation Example 430

N-(2-Hydroxyethyl)-N-methylsulfuric diamide (780 mg), DMAP (309 mg),triethylamine (0.85 mL), and tert-butyl (chloro)dimethylsilane (915 mg)were sequentially added to DMF (8 mL), followed by stirring at roomtemperature overnight. To the reaction mixture was added an appropriateamount of a saturated aqueous ammonium chloride solution, followed byextraction with CHCl₃, and the organic layer was washed with brine anddried over MgSO₄. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to prepare N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methylsulfuric diamide (801 mg) as a whitesolid.

Preparation Example 431

Ethyl(2R)-[4-(benzyloxy)phenyl]{[2-(trimethylsilyl)ethoxy]methoxy}acetate(2.65 g), cyclohexene (20 mL), and 10% palladium/carbon (530 mg) wereadded to EtOH (40 mL), followed by stirring at 100° C. for 2 hours. Theinsoluble material was filtered through Celite, and the obtainedfiltrate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane to hexane:ethylacetate=2:1) to prepare ethyl (2R)-(4-hydroxyphenyl){[2-(trimethylsilyl)ethoxy]methoxy}acetate (2.0 g) as a colorless oilysubstance.

Preparation Example 432

[2-(1,3-Dioxo-1,3-dihydro 2H-isoindol-2-yl)ethyl](triphenyl)phosphoniumbromide (4.0 g), 3-(difluoromethyl)benzaldehyde (1.1 g), and sodiumhydride (0.37 g) were added to DMSO (20 mL), followed by stirring atroom temperature for 2 hours under an argon gas atmosphere. Anappropriate amount of ice water and a saturated aqueous ammoniumchloride solution were poured into the reaction mixture, followed byextraction with ethyl acetate. The obtained organic layer was washedwith brine and dried over MgSO₄, the solvent was evaporated underreduced pressure, and the obtained yellow oily residue was purified bysilica gel column chromatography (hexane:ethyl acetate=3:1) to prepare2-{3-[3-(difluoromethyl)phenyl]prop-2-en-1-yl}-1H-isoindole-1,3(2H)-dione(1.47 g) as a yellow oily substance.

Preparation Example 437

2-{3-[3-(Difluoromethyl)phenyl]prop-2-en-1-yl}-1H-isoindole-1,3(2H)-dione(1.4 g) and 10% palladium/carbon (0.53 g; 55% wet) were sequentiallyadded to an MeOH/ethyl acetate (3:1) solution (40 mL), followed bystirring at a normal temperature/a normal pressure for about 2 hoursunder a hydrogen gas atmosphere. The catalyst was filtered throughCelite, and the obtained filtrate was evaporated under reduced pressureto prepare,2-{3-[3-(difluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (1.41g) as a white solid.

Preparation Example 440

2-{3-[3-(Difluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (1.4g) and hydrazine hydrate (0.65 mL) were added to EtOH (14 mL), byheating at 90° C. for about 1.5 hours. The reaction mixture was left tobe cooled, and the insoluble material was removed by filtration whilediluting and washing with an appropriate amount of diethyl ether, andthe obtained filtrate was concentrated. The residue was diluted with anappropriate amount of diethyl ether, an appropriate amount of MgSO₄ wasadded thereto, and the precipitated insoluble material was removed byfiltration. The obtained filtrate was evaporated under reduced pressureto prepare 3-[3-(difluoromethyl)phenyl]propan-1-amine (0.74 g) as acolorless oily substance.

Preparation Example 443

With reference to the method of Lesac, et al. (Tetrahedron Asymmetry2003, 14, 2731-2737), 4-methoxy-2-methylbenzaldehyde (10 g),N-benzyl-N,N,N-triethyl ammonium chloride (0.76 g) and a 50% aqueousNaOH solution (40 mL) were sequentially added to CHCl₃ (20 mL), followedby stirring at room temperature for 8 hours. The insoluble material wasfiltered, and the obtained filtrate was diluted with an appropriateamount of purified water and washed with diethyl ether. The aqueouslayer was acidified with 1 M hydrochloric acid and then extracted withethyl acetate. The organic layer was washed with brine and dried overNa₂SO₄, and then the solvent was evaporated under reduced pressure toprepare hydroxy(4-methoxy-2-methylphenyl)acetic acid (8.0 g) as a palebrown solid.

Preparation Example 445

Hydroxy(4-methoxy-2-methylphenyl)acetic acid (3.05 g) and(1R)-1-(1-naphthyl)ethanamine (0.27 g) were sequentially added toisopropyl alcohol (10 mL), followed by stirring at room temperature for5 hours. The precipitated solid was collected by filtration andsolidified with isopropyl alcohol. To this solid was added anappropriate amount of purified water and adjusted to be weakly acidicwith 1 M hydrochloric acid, followed by extraction with ethyl acetate.The organic layer was washed with brine, and subsequently dried overNa₂SO₄, and the solvent was evaporated under reduced pressure to prepare(2R)-hydroxy(4-methoxy-2-methylphenyl)acetic acid (0.8 g) as a whitesolid.

Preparation Example 447

(2R)-Hydroxy(4-methoxy-2-methylphenyl)acetic acid (183 mg), potassiumcarbonate (150 mg), and ethyl iodide (193 mg) were sequentially added toDMF (5 mL), followed by stirring at room temperature for 3 hours. To thereaction mixture was added an appropriate amount of purified water,followed by extraction with ethyl acetate, and the organic layer waswashed with brine, and subsequently dried over Na₂SO₄. The solvent wasevaporated under reduced pressure to prepare ethyl(2R)-hydroxy(4-methoxy-2-methylphenyl)acetate (150 mg) as a yellow oilysubstance.

Preparation Example 448

Ethyl (2R)-hydroxy(4-methoxy-2-methylphenyl)acetate (0.98 g),[2-(chloromethoxy)ethyl](trimethyl) silane (1.54 mL), a Hunig's base(1.5 mL), and tetra-n-butylammonium iodide (1.61 g) were sequentiallyadded to methylene chloride (10 mL), followed by stirring at roomtemperature overnight. The reaction mixture was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane to hexane:ethyl acetate=5:1) to prepare ethyl(2R)-(4-methoxy-2-methylphenyl){[2-(trimethylsilyl)ethoxy]methoxy}acetate(934 mg) as a colorless oily substance.

Next, ethyl (2R)-(4-methoxy-2-methylphenyl){[2-(trimethylsilyl)ethoxy]methoxy}acetate and a 1 M aqueous NaOHsolution (5 mL) were sequentially added to an EtOH/THF (1:1) solution(16 mL), followed by stirring at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure, and the residue wasadjusted to a neutral solution by the addition of an appropriate amountof 1 M hydrochloric acid, followed by extraction with ethyl acetate. Theorganic layer was washed with brine and dried over Na₂SO₄, and then thesolvent was evaporated under reduced pressure to prepare (2R)-(4-mmethoxy-2-methylphenyl) {[2-(trimethylsilyl)ethoxy]methoxy}acetic acid(870 mg) as a colorless oily substance.

Preparation Example 449

Hydroxy(6-methoxypyridin-3-yl)acetic acid (1.37 g) was added to EtOH (10mL), warmed, and dissolved therein, and then (1R)-1-phenethylethylamine(0.95 g) was added thereto, followed by stirring at room temperature for3 hours. The precipitated solid was collected by filtration and added toan appropriate amount of purified water, followed by adjustment to aweakly acidic solution with 1 M hydrochloric acid and then extractionwith ethyl acetate twice. The organic layer was washed with brine anddried over Na₂SO₄, and then the solvent was evaporated under reducedpressure to prepare (2R)-hydroxy(6-methoxypyridin-3-yl)acetic acid (0.33g).

Next, (2R)-hydroxy(6-methoxypyridin-3-yl)acetic acid (0.33 g), potassiumcarbonate (0.5 g), and ethyl iodide (0.56 g) were sequentially added toDMF (5 mL), followed by stirring at room temperature for 5 hours. To thereaction mixture was added an appropriate amount of ice water, followedby extraction with ethyl acetate, and the organic layer was washed withbrine and dried over Na₂SO₄. The solvent was evaporated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane→hexane:ethyl acetate=1:1) to prepare ethyl(2R)-hydroxy(6-methoxypyridin-3-yl)acetate (0.28 g) as a yellow oilysubstance.

Preparation Example 450

Ethyl2-[([3-(3-bromophenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxylate(280 mg), ethynyl(trimethyl) silane (0.17 mL), copper iodide (9.3 mg),and bis(triphenylphosphine) palladium(II) dichloride (34 mg) weresequentially added to triethylamine (2.8 mL), followed by warming at 70°C. for 20 hours under a sealed argon gas. The reaction mixture wasdiluted with an appropriate amount of ethyl acetate, the black insolublematerial was removed by filtration through Celite, and the obtainedorganic layer was sequentially washed with unsaturated sodiumbicarbonate water and brine. The organic layer was dried over MgSO₄, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (ethylacetate:hexane=1:1) to prepare ethyl2-{[{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}(3-{3-[(trimethylsilyl)ethynyl]phenyl}propyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylate(160 mg).

Preparation Example 451

Ethyl2-{[{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}(3-{3-[(trimethylsilyl)ethynyl]phenyl}propyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylate(150 mg) and potassium carbonate (42 mg) were added to methanol (2 mL),followed by stirring at room temperature for about 2.5 hours. Thereaction mixture was concentrated under reduced pressure, and to theresidue was added an appropriate amount of purified water, followed byextraction with ethyl acetate. The organic layer was washed with brineand dried over MgSO₄, and then the solvent was evaporated. The resultingresidue was purified by silica gel column chromatography (ethylacetate:hexane=3:2) to prepare methyl2-[([3-(3-ethynylphenyl)propyl]{[145-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxylate(100 mg).

Preparation Example 452

Ethyl2-[([3-(3-bromophenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxylate(300 mg), a 2,4,6-trivinylcyclotriboroxane-pyridine complex (133 mg),palladium acetate (24 mg), tricyclohexylphosphine (59 mg), and potassiumphosphate (334 mg) were sequentially added to a dioxane/water (10:1)(6.6 mL) solution, followed by heating at 95° C. for 2.5 days. Theinsoluble material was removed by filtration through Celite whilediluting and washing the reaction mixture with an appropriate amount ofethyl acetate and purified water. The filtrate was subjected toliquid-separation, and the obtained organic layer was washed with brineand dried over MgSO₄, and then evaporated under reduced pressure. Theobtained brown residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to prepare ethyl2-[({[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}[3-(3-vinylphenyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxylate(245 mg) as a colorless oily substance.

Preparation Example 453

(2R)-(2-Fluoro-4-methoxyphenyl)(hydroxy)acetic acid (1.1 g), potassiumcarbonate (0.9 g), and ethyl iodide (0.6 mL) were sequentially added toDMF (30 mL), followed by stirring at room temperature for 3 hours. Tothe reaction mixture was added an appropriate amount of purified water,followed by extraction with ethyl acetate. The organic layer was washedwith brine and dried over Na₂SO₄, and then the solvent was evaporatedunder reduced pressure to prepare ethyl(2R)-(2-fluoro-4-methoxyphenyl)(hydroxy)acetate (1.2 g).

Next, ethyl (2R)-(2-fluoro-4-methoxyphenyl)(hydroxy)acetate (270mg),[2-(chloromethoxy)ethyl](trimethyl) silane (0.42 mL), a Hunig's base(0.42 mL), and tetra-n-butylammonium iodide (440 mg) were sequentiallyadded to methylene chloride (10 mL), followed by stirring at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane to hexane:ethyl acetate=5:1) to prepareethyl(2R)-(2-fluoro-4-methoxyphenyl){[2-(trimethylsilyl)ethoxy]methoxy}acetate(325 mg) as a colorless oily substance.

Preparation Example 454

Ethyl5-bromo-2-[(4R)-4-(4-methoxyphenyl)-10,10-dimethyl-3-oxo-2-(3-phenylpropyl)-5,7-dioxo-2-aza-10-silaneundec-1-yl]-1,3-thiazole-4-carboxylate(420 mg), tributyl(vinyl)tin (0.27 mL),(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (60 mg), andtris(2-methylphenyl)phosphine (75 mg) were sequentially added to toluene(10 mL), followed by stirring at 80° C. for 2 hours. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography (hexane to hexane:ethyl acetate=1:1)to prepare ethyl2-[(4R)-4-(4-methoxyphenyl)-10,10-dimethyl-3-oxo-2-(3-phenylpropyl)-5,7-dioxo-2-aza-10-silaneundec-1-yl]-5-vinyl-1,3-thiazole-4-carboxylate(319 mg) as a colorless oily substance.

Preparation Example 455

Using the same condition as the method of Preparation Example 5 asdescribed above, preparation was performed.

Preparation Example 456

N-(2-{[tert-butyl (dimethyl)silyl]oxy}ethyl)-N-ethylsulfamide wasprepared from 2-(ethylamino)ethanol by carrying out the reactionssuccessively and sequentially using the same methods of PreparationExample 41, Preparation Example 35, and Preparation Example 430.

The compounds of Preparation Examples shown in Tables below wereprepared using the respective corresponding starting materials in thesame manner as the methods of Preparation Examples above. Thestructures, the preparation methods, and the physicochemical data forthe compounds of Preparation Examples are shown in Tables below.

TABLE 4 Rf Syn Structure  1 R1 

 2 R2 

 3 R3 

 4 R4 

 5 R5 

 6 R6 

 7 R7 

 8 R8 

 9 R9 

10 R10

11 R11

12 R12

TABLE 5 Rf Syn Structure 13 R13

14 R14

15 R15

16 R16

17 R17

18 R18

19 R19

20 R20

21 R21

22 R22

23 R23

24 R24

TABLE 6 Rf Syn Structure 25 R25

26 R26

27 R27

28 R28

29 R29

30 R30

31 R31

32 R32

33 R33

34 R34

35 R35

36 R36

TABLE 7 Rf Syn Structure 37 R37

38 R38

39 R39

40 R40

41 R41

42 R42

43 R43

44 R44

45 R45

46 R46

47 R47

48 R48

TABLE 8 Rf Syn Structure 49 R49

50 R50

51 R51

52 R52

53 R53

54 R54

55 R35

56 R30

57 R3 

58 R3 

59 R5 

60 R5 

61 R5 

62 R5 

TABLE 9 Rf Syn Structure 63 R5 

64 R5 

65 R5 

66 R5 

67 R5 

68 R5 

69 R5 

70 R5 

71 R7 

72 R11

73 R12

74 R21

TABLE 10 Rf Syn Structure 75 R30

76 R25

77 R26

78 R26

79 R26

80 R29

81 R29

82 R33

83 R35

84 R35

85 R35

86 R35

87 R35

88 R35

TABLE 11 Rf Syn Structure  90 R35

 91 R35

 92 R35

 93 R93

 94 R36

 95 R39

 96 R39

 97 R41

 98 R42

 99 R42

100 R42

101 R42

TABLE 12 Rf Syn Structure 102 R42 

103 R42 

104 R42 

105 R42 

106 R106

107 R106

108 R106

109 R106

110 R106

111 R106

TABLE 13 Rf Syn Structure 112 R106

113 R106

114 R106

115 R106

116 R106

117 R106

118 R49

119 R50

120 R50

121 R50

TABLE 14 Rf Syn Structure 122 R50

123 R34

124 R4

125 R28

126 R7

127 R42

89 R35

128 R5

129 R5

130 R5

131 R5

132 R5

TABLE 15 Rf Syn Structure 133 R5

134 R5

135 R5

136 R5

137 R5

138 R5

139 R5

140 R5

141 R5

142 R5

TABLE 16 Rf Syn Structure 143 R5

144 R5

145 R5

146 R5

147 R5

148 R5

149 R5

150 R5

151 R5

152 R5

TABLE 17 Rf Syn Structure 153 R5

154 R5

155 R5

156 R5

157 R5

158 R5

159 R5

160 R5

161 R5

162 R5

163 R5

164 R5

TABLE 18 Rf Syn Structure 165 R42

166 R42

167 R42

168 R42

169 R42

170 R42

171 R42

172 R42

173 R42

174 R42

TABLE 19 Rf Syn Structure 175 R42

176 R42

177 R42

178 R42

179 R42

180 R42

181 R42

182 R42

183 R42

184 R26

185 R26

186 R26

TABLE 20 Rf Syn Structure 187 R26

188 R26

189 R26

190 R26

191 R26

192 R26

193 R26

194 R26

195 R26

196 R26

197 R26

198 R26

TABLE 21 Rf Syn Structure 199 R44

200 R44

201 R44

202 R44

203 R44

204 R44

205 R44

206 R44

207 R44

208 R44

209 R44

210 R44

TABLE 22 Rf Syn Structure 211 R44

212 R44

213 R44

214 R44

215 R44

216 R216

217 R39

218 R39

219 R219

220 R4

221 R5

222 R5

TABLE 23 Rf Syn Structure 224 R5

225 R5

226 R5

227 R5

228 R5

229 R5

230 R5

231 R5

232 R5

233 R5

TABLE 24 Rf Syn Structure 234 R5

235 R5

236 R5

237 R5

238 R5

239 R5

240 R5

241 R5

242 R5

243 R5

TABLE 25 Rf Syn Structure 244 R5

245 R5

246 R5

247 R5

248 R5

249 R5

250 R5

251 R5

252 R5

253 R5

TABLE 26 Rf Syn Structure 254 R5

255 R5

256 R5

257 R5

258 R5

259 R5

260 R5

261 R5

262 R5

263 R5

264 R5

265 R5

TABLE 27 Rf Syn Structure 266 R5

267 R5

268 R5

269 R5

270 R5

271 R5

272 R5

273 R5

274 R5

275 R5

TABLE 28 Rf Syn Structure 276 R5

277 R5

278 R5

279 R5

280 R5

281 R5

282 R4

283 R5

221 R4

284 R5

285 R5

286 R5

287 R5

288 R6

TABLE 29 Rf Syn Structure 289 R6

290 R6

291 R8

293 R8

294 R9

295 R9

296 R9

297 R10

298 R12

299 R12

300 R13

301 R20

TABLE 30 Rf Syn Structure 302 R20

303 R26

304 R26

305 R28

306 R28

307 R28

308 R30

309 R30

310 R30

311 R30

312 R30

313 R30

314 R33

315 R34

316 R34

317 R34

318 R34

319 R39

TABLE 31 Rf Syn Structure 320 R39

321 R39

322 R39

323 R39

324 R39

325 R39

326 R39

327 R39

328 R39

329 R39

330 R39

331 R39

332 R39

333 R39

334 R39

335 R39

336 R39

337 R39

338 R39

339 R39

TABLE 32 Rf Syn Structure 340 R39

341 R39

292 R8

342 R39

343 R39

344 R39

345 R39

346 R39

347 R39

348 R39

349 R40

350 R40

351 R44

352 R44

353 R44

354 R44

TABLE 33 Rf Syn Structure 355 R44

356 R44

357 R44

358 R44

359 R44

360 R44

361 R44

362 R44

363 R44

364 R44

TABLE 34 Rf Syn Structure 365 R44

366 R44

367 R44

368 R44

369 R44

370 R44

371 R44

372 R44

374 R44

375 R44

376 R44

377 R44

TABLE 35 Rf Syn Structure 378 R44

379 R44

380 R44

381 R44

382 R44

383 R44

384 R44

385 R44

386 R44

387 R44

TABLE 36 Rf Syn Structure 388 R44

389 R44

390 R44

391 R44

392 R44

393 R44

394 R44

395 R44

396 R44

397 R44

398 R49

399 R53

400 R400

401 R401

TABLE 37 Rf Syn Structure 402 R402

403 R403

404 R405

405 R405

406 R405

407 R408

408 R408

409 R408

373 R44

410 R408

411 R411

412 R411

413 R411

414 R411

415 R411

416 R411

TABLE 38 Rf Syn Structure 417 R411

418 R411

419 R411

420 R420

421 R421

422 R421

423 R421

424 R424

425 R425

426 R425

427 R425

428 R425

429 R429

430 R430

TABLE 39 Rf Syn Structure 431 R431

432 R432

433 R432

434 R432

435 R432

436 R437

437 R437

438 R437

439 R437

440 R440

441 R440

442 R440

443 R443

444 R443

445 R445

446 R445

TABLE 40 Rf Syn Structure 447 R447

448 R448

449 R449

450 R450

451 R451

452 R452

453 R453

454 R454

455 R455

456 R456

TABLE 41 Rf Data 1 [ESI+]: 211 2 [ESI+]: 527 3 [ESI+]: 209 4 [EI+]: 3765 [FAB+]: 441 6 [ESI+]: 157 7 [EI+]: 184 8 [ESI+]: 194 9 [ESI+]: 225 10[ESI+]: 655 11 [EI+]: 236 12 [ESI+]: 251 13 [ESI+]: 508 14 [EI+]: 308 15[ESI+]: 527 16 [ESI+]: 239 17 [FAB+]: 511 18 [ESI+]: 439 19 [ESI+]: 14920 [ESI+]: 175 21 [ESI+]: 233 22 [ESI+]: 250 23 [EI+]: 249, 251 24[ESI+]: 328, 330, 332 25 [ESI+]: 206, 208 26 [FAB+]: 305 27 [ESI+]: 28928 [ESI+]: 405 29 [ESI+]: 627 30 [ESI+]: 383 31 [ESI+]: 466 32 [ESI+]:541 33 [EI+]: 199

TABLE 42 Rf Data 34 [ESI+]: 483 35 [ESI+]: 167 36 [FAB+]: 274 37 [EI+]:226 38 [ESI+]: 513 39 [FAB+]: 319 40 [ESI+]: 255 41 [ESI+]: 299 42[ESI+]: 483 43 [ESI+]: 583 44 [ESI+]: 497 45 [EI+]: 266 46 [ESI+]: 21147 [FAB+]: 483 48 NMR-CDCl₃: 3.82 (3H, s), 3.84 (3H, s), 6.50 (1H, s),6.57 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.6 Hz). 49 [ESI−]: 199 50NMR-DMSO-d₆: 3.73 (3H, s), 4.81 (2H, s), 7.24-7.36 (5H, m), 7.81 (2H,br) 51 [ESI+]: 273 52 [ESI+]: 239 53 [ESI+]: 225 54 [ESI+]: 254 55[ESI+]: 483 56 [ESI+]: 383 57 [ESI+]: 223 58 [EI+]: 294 59 [FAB+]: 46960 [ESI+]: 533, 535 61 [ESI+]: 489, 491 62 [FAB+]: 481 63 [ESI+]: 480 64[ESI+]: 599 65 [ESI+]: 499

TABLE 43 Rf Data 66 [FAB+]: 454 67 [ESI+]: 439 68 [ESI+]: 438 69 [FAB+]:437 70 [ESI+]: 481 71 NMR-DMSO-d₆: 3.76-3.86 (2H, m), 3.76-3.86 (2H, m),3.93-4.02 (2H, m), 5.20-5.37 (1H, m), 7.07 (2H, brs) 72 [ESI+]: 509 73[ESI+]: 509 74 [ESI+]: 533 75 [ESI+]: 397 76 [FAB+]: 285, 287 77 [ESI+]:383, 385 78 [ESI+]: 339 79 [ESI+]: 305 80 [ESI+]: 281 81 [ESI+]: 267 82[APCI+]: 186 83 [ESI+]: 225 84 [EI+]: 182 85 [ESI+]: 173 86 [ESI+]: 20187 [ESI+]: 227 88 [ESI+]: 241 89 [ESI+]: 311 90 [FAB+]: 283 91 [FAB+]:413 92 93 [ESI+]: 717 94 [FAB+]: 260 95 [ESI+]: 290 96 [ESI+]: 289 97[ESI−]: 285

TABLE 44 Rf Data 98 [ESI+]: 561, 563 99 [FAB+]: 517 100 [FAB+]: 468 101[FAB+]: 467 102 [ESI+]: 451 103 [ESI+]: 547, 549 104 [ESI+]: 483 105[ESI+]: 467 106 [ESI+]: 427 107 [ESI+]: 441 108 [ESI+]: 455 109 [ESI+]:489 110 [ESI+]: 505 111 [ESI+]: 517 112 [ESI+]: 414 113 [ESI+]: 471 114[ESI+]: 453 115 [ESI+]: 469 116 [ESI+]: 469 117 [ESI+]: 470 118 [ESI+]:184 119 NMR-DMSO-d₆: 3.71 (3H, s), 3.74 (3H, s), 7.18 (2H, br) 120NMR-CDCl₃: 3.39 (3H, s), 3.56 (2H, t, J = 5.2 Hz), 3.88 (3H, s), 4.00(2H, t, J = 5.2 Hz), 5.49 (2H, br) 121 NMR-CDCl₃: 2.30-2.41 (1H, m),2.71-2.83 (1H, m), 3.86-3.94 (4H, m), 4.29 (1H, dd, J = 9.0 Hz, 15.0Hz), 4.67 (2H, t, J = 7.3 Hz), 4.91-5.00 (1H, m), 5.71 (2H, br) 122[ESI−]: 193 123 [ESI+]: 497 124 [ESI+]: 391 125 [ESI+]: 419 126 [EI+]290 127 [ESI+]: 497 128 [ESI+]: 495, 497

TABLE 45 Rf Data 129 [ESI+]: 459 130 [FAB+]: 491 131 [FAB+]: 473 132[FAB+]: 491 133 [FAB+]: 491 134 [FAB+]: 473 135 [ESI+]: 507, 509 136[FAB+]: 480 137 [ESI+]: 487 138 [ESI+]: 469 139 [FAB+]: 469 140 [ESI+]:481 141 [ESI+]: 467 142 [FAB+]: 481 143 [FAB+]: 481 144 [ESI+]: 465 145146 [ESI+]: 469 147 [ESI+]: 461 148 [FAB+]: 488 149 [ESI+]: 491 150[ESI+]: 475 151 [FAB+]: 487 152 [ESI+]: 485, 487 153 [ESI+]: 475 154[ESI+]: 459 155 [FAB+]: 483 156 [FAB+]: 455 157 [FAB+]: 505 158 [ESI+]:495 159 [ESI+]: 489, 491 160 [FAB+]: 567 161 [FAB+]: 499

TABLE 46 Rf Data 162 [FAB+]: 509 163 [FAB+]: 503 164 165 [ESI+]: 523,525 166 [FAB+]: 487 167 [FAB+]: 519 168 [FAB+]: 501 169 [ESI+]: 519 170[ESI+]: 519 171 [ESI+]: 501 172 173 [FAB+]: 508 174 [ESI+]: 515 175[ESI+]: 497 176 177 178 [ESI+]: 516 179 180 181 [ESI+]: 515 182 [FAB+]:503 183 [FAB+]: 483 184 [ESI+]: 345 185 [EI+] 308 186 [EI+] 340 187[CI+]: 323 188 [FAB+]: 341 189 [ESI+]: 341 190 [ESI+]: 323 191 192[CI+]: 330 193 [ESI+]: 337 194

TABLE 47 Rf Data 195 196 197 198 [ESI+]: 339, 341 199 200 NMR-CDCl₃:1.41 (3H, t, J = 7.1 Hz), 1.60 (2H, brs), 1.91 (2H, br), 2.44 (2H, br),3.44 (2H, br), 3.81 (6H, s), 4.44 (2H, q, J = 7.1 Hz), 5.02 (1H, br),5.51 (1H, dd, J = 2.5, 12 Hz), 6.22 (1H, d, J = 18 Hz), 6.55 (2H, brs),6.84-7.03 (2H, m), 7.08-7.25 (3H, m), 8.19 (1H, s). 201 [ESI+]: 509 202[FAB+]: 547 203 204 [FAB+]: 537 205 [ESI+]: 517, 519 206 [ESI+]: 487 207[ESI+]: 511 208 [ESI+]: 533 209 [ESI+]: 523 210 [ESI+]: 517, 519 211[ESI+]: 595 212 [ESI+]: 527 213 [ESI+]: 537, 539 214 [ESI+]: 531, 533215 216 [ESI+]: 511 217 [ESI+]: 338 218 [ESI+]: 337 219 NMR-DMSO-d₆:1.88 (2H, br), 2.01 (3H, s), 2.41-2.60 (2H, m), 3.34-3.42 (2H, m), 3.75(6H, s), 4.96 (2H, br), 6.61 (2H, br), 7.01-7.16 (5H, m), 7.61-7.66 (2H,m), 8.23 (1H, s). [FAB+]: 454 220 [ESI+]: 391 221 [ESI+]: 433, 435 (M +23) 222 [ESI+]: 465

TABLE 48 Rf Data 223 [ESI+]: 466 224 [ESI+]: 495 225 [ESI+]: 385 (M +23) 226 [ESI+]: 469 227 [ESI−]: 357 228 [ESI+]: 483 229 [ESI+]: 505, 507230 [ESI+]: 485 231 [ESI+]: 195 232 [ESI+]: 194 233 [ESI+]: 483 234[ESI+]: 479 235 [ESI−]: 379 236 [FAB−]: 313 237 [ESI+]: 483 238 [ESI+]:480 239 [ESI+]: 506, 508 240 [ESI+]: 484 241 [ESI+]: 500 242 [ESI+]: 483243 [ESI+]: 491 244 [ESI+]: 586 245 [ESI+]: 472 246 [ESI+]: 470 247[ESI+]: 211 248 [ESI+]: 516 249 [ESI+]: 490, 492 250 [ESI+]: 456 251[ESI+]: 603 252 [ESI+]: 552 253 [ESI+]: 494 254 [ESI+]: 603 255 [ESI+]:585

TABLE 49 Rf Data 256 [ESI+]: 434 257 [ESI+]: 484 258 [ESI+]: 498 259[ESI+]: 591 260 [ESI+]: 498 261 [ESI+]: 600 262 [ESI+]: 471 263 [ESI+]:544, 546 264 [ESI+]: 500, 502 265 [ESI+]: 522 266 [APCI+]: 476 267[ESI+]: 471 268 [ESI+]: 472 269 [ESI+]: 455 270 [ESI+]: 506 271 [ESI+]:490 272 [ESI+]: 506 273 [ESI+]: 492 274 [ESI+]: 603 275 [ESI+]: 609 276[FAB−]: 601 277 [ESI+]: 483 278 [ESI+]: 484 279 [ESI+]: 506 280 [FAB+]:649, 651 281 [ESI+]: 599 282 [ESI+]: 433, 435 (M + 23) 283 [ESI−]: 343284 [FAB−]: 311 285 [FAB−]: 312 286 [FAB−]: 312 287 [ESI+]: 353 (M + 23)

TABLE 50 Rf Data 288 NMR-CDCl₃: 1.24 (2H, m), 1.65 (2H, m), 3.37 (3H,s), 4.43 (2H, s), 7.26 (2H, m), 7.32 (2H, m). 289 [ESI+]: 157 290[APCI]: 155 291 [ESI+]: 194 292 [ESI+]: 211 293 [ESI+]: 194 294 [ESI+]:561 295 [ESI+]: 576 296 [ESI+]: 590 297 NMR-CDCl₃: 1.08 (2H, m), 1.36(9H, s), 1.52 (2H, m), 7.19 (2H, m), 7.41 (2H, m). 298 [ESI+]: 534 299[ESI+]: 534 300 [APCI+]: 504 301 [APCI+]: 175 302 [ESI+]: 192 303[ESI+]: 383, 385 304 [ESI+]: 339 305 [ESI+]: 510, 512 (M + 23) 306[ESI+]: 461, 463 (M + 23) 307 [ESI+]: 437 308 [ESI+]: 397 309 [ESI+]:417, 419 310 [ESI+]: 368 311 [ESI+]: 369 312 [ESI+]: 415 313 [ESI+]:388, 390 314 [EI]: 199 315 [APCI−]: 466 316 [ESI+]: 539, 541 (M + 23)317 [ESI+]: 515 318 [ESI+]: 469 319 [ESI+]: 349

TABLE 51 Rf Data 320 [ESI+]: 353, 355 321 [ESI+]: 323 322 [ESI+]: 337323 324 [ESI+]: 339 325 [ESI+]: 337 326 [ESI+]: 333 327 [ESI+]: 337 328[ESI+]: 337 329 [ESI+]: 333 330 [ESI+]: 359, 361 331 [ESI+]: 353 332[ESI+]: 337 333 [ESI+]: 345 334 [ESI+]: 369 335 [ESI+]: 343, 345 336[ESI+]: 309 337 [ESI+]: 337 338 [ESI+]: 405 339 [ESI+]: 347 340 [ESI+]:337 341 [ESI+]: 288 342 [ESI+]: 351 343 [ESI+]: 351 344 [ESI+]: 325 345[ESI+]: 397, 399 346 [ESI+]: 375 347 NMR-CDCl₃: 1.41 (3H, t, J = 7.1Hz), 1.58 (1H, br), 1.84 (2H, m), 3.49 (1H, s), 4.05 (2H, s), 4.41 (2H,q, J = 7.1 Hz), 6.93 (1H, d, J = 4.3 Hz), 7.25 (2H, m). 348 [ESI+]: 359349 [ESI−]: 255 350 [EI]: 254 351 [ESI+]: 494

TABLE 52 Rf Data 352 [ESI+]: 523 353 [ESI+]: 497 354 [ESI+]: 498 355[ESI+]: 511 356 [ESI+]: 533, 535 357 [ESI+]: 512 358 [ESI+]: 511 359[ESI+]: 507 360 [ESI+]: 511 361 [ESI+]: 512 362 [ESI+]: 508 363 [ESI+]:534, 536 364 [ESI+]: 512 365 [ESI+]: 528 366 [ESI+]: 511 367 [ESI+]: 613368 [ESI+]: 519 369 [ESI+]: 614 370 [ESI+]: 500 371 [ESI+]: 544 372[ESI+]: 518 373 [ESI+]: 484 374 [ESI+]: 631 375 [ESI+]: 512 376 [ESI+]:580 377 [ESI+]: 522 378 [ESI+]: 631 379 [ESI+]: 462 380 [ESI+]: 526 381[ESI+]: 619 382 [ESI+]: 526 383 [ESI+]: 499 384 [ESI+]: 628

TABLE 53 Rf Data 385 [ESI+]: 572, 574 386 [ESI+]: 528, 530 387 [ESI+]:550 388 [ESI+]: 499 389 [ESI+]: 500 390 [ESI+]: 483 391 [ESI+]: 631 392[ESI+]: 637 393 [ESI+]: 631 394 [ESI+]: 511 395 [ESI+]: 534 396 [ESI+]:701, 699 (M + 23) 397 [ESI+]: 557, 559 398 [ESI−]: 199 399 [ESI+]: 225400 NMR-CDCl₃: 1.15 (2H, m), 1.36 (9H, s), 1.58 (2H, m), 7.49 (2H, m),7.81 (2H, m), 9.99 (1H, s). 401 NMR-CDCl₃: 1.10 (2H, m), 1.36 (9H, s),1.52 (2H, m), 2.04 (1H, br), 4.67 (2H, d, J = 5.6 Hz), 7.28-7.34 (4H,m). 402 NMR-CDCl₃: 1.10 (2H, m), 1.36 (9H, s), 1.51 (2H, m), 3.37 (3H,s), 4.43 (2H, s), 7.25 (2H, m), 7.31 (2H, m). 403 [ESI+]: 209 404[ESI+]: 364 (M + 23) 405 [ESI+]: 187 406 [ESI+]: 205 407 [ESI+]: 265(M + 23) 408 [ESI+]: 283 (M + 23) 409 [ESI+]: 279 (M + 23) 410 [ESI+]:301 (M + 23) 411 [ESI+]: 413 (M + 23) 412 [ESI+]: 409 (M + 23) 413[ESI+]: 431 (M + 23) 414 [ESI+]: 365 (M + 23) 415 [ESI+]: 395 (M + 23)

TABLE 54 Rf Data 416 NMR-CDCl₃: −0.01 (9H, s), 0.87-0.92 (2H, m), 1.21(3H, t, J = 7.1 Hz), 3.54-3.73 (2H, m), 3.80 (3H, s), 4.11-4.25 (2H, m),4.68-4.78 (2H, m), 5.11 (1H, s), 6.88 (2H, d, J = 8.6 Hz), 7.36 (2H, d,J = 8.6 Hz). 417 ESI+: 439 (M + 23) 418 [ESI+]: 342 419 [ESI+]: 497 420[ESI+]: 183 421 [ESI−]: 615 422 [ESI+]: 613 423 [ESI+]: 620, 622 424[ESI−]: 205 425 [ESI+]: 245 (M + 23) 426 [ESI+]: 244 (M + 23) 427[ESI+]: 239 428 NMR-CDCl₃: 1.42 (3H, t, J = 7.2 Hz), 3.86 (1H, s), 4.43(2H, q, J = 7.2 Hz), 6.96-6.99 (2H, m), 7.99-8.02 (2H, m). 429 [ESI+]:235 (M + 23) 430 NMR-CDCl₃: 0.10 (6H, s), 0.91 (9H, s), 2.92 (3H, s),3.39 (2H, t, J = 4.8 Hz), 3.80 (2H, t, J = 4.8 Hz), 4.72 (2H, br). 431[FAB−]: 325 432 [CI+]: 314 433 [ESI+]: 296 434 [ESI+]: 318 435 [ESI+]:292 436 [ESI+]: 627 437 EI: 315 438 [ESI+]: 298 439 [ESI+]: 322 440[ESI+]: 186 441 [ESI+]: 168 442 [ESI+]: 192 443 [ESI−]: 195 444 [ESI+]:184 445 [ESI+]: 219 (M + 23)

TABLE 55 Rf Data 446 [ESI−]: 199 447 [EI]: 224 448 [FAB−]: 325 449[ESI+]: 212 450 [ESI+]: 590 451 [ESI+]: 504 452 [ESI+]: 520 453 [ESI+]:381 (M + 23) 454 [ESI+]: 625 455 [ESI+]: 409 456 [ESI+]: 283

Example 1

N-[(Dimethylamino)sulfonyl]-2-{[(3-phenylpropyl)amino]methyl}5-methyl-1,3-thiazole-4-carboxamide hydrochloride (100 mg),1-(4-methoxyphenyl)cyclobutanecarboxylic acid (50 mg), triethylamine(0.15 mL), and HATU (120 mg) were added to acetonitrile (3.5 mL),followed by stirring at room temperature for 5 hours. The reactionmixture was concentrated under reduced pressure, and to the obtainedresidue were added water and 1 M hydrochloric acid, followed byextraction with CHCl₃. The organic layer was dried over Na₂SO₄, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:3)to prepareN-[(dimethylamino)sulfonyl]-2-{[{[1-(4-methoxyphenyl)cyclobutyl]carbonyl}(3-phenylpropyl)amino]methyl}-5-methyl-1,3-triazole-4-carboxamide(47 mg).

Example 2

To a mixture ofN-[(dimethylamino)sulfonyl]-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamidehydrochloride (10.5 mg), 3,5-diethoxybenzoic acid (6.3 mg),triethylamine (10.4 μL), and DMF (0.50 mL) was added a HATU (11.4mg)/DMF (0.10 mL) solution at room temperature, followed by stirringovernight. To the reaction mixture was added an appropriate amount ofpurified water, followed by extraction with CHCl₃. The organic layer wasconcentrated under reduced pressure, and the obtained residue waspurified by preparative high performance liquid chromatography(MeOH/0.1% aqueous formic acid solution) to prepare2-{[(3,5-diethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-[(dimethylamino)sulfonyl]-1,3-thiazole-4-carboxamide(9.2 mg).

Example 3

N-({[(2-{[(3,5-3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-methylglycine(0.19 g) was prepared from methylN-({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-methylglycinate(0.22 g) in the same manner as the method of Preparation Example 5.

Example 4

5-(Difluoromethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (40 mg) was prepared from ethyl5-(difluoromethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylate(60 mg) in the same manner as in Preparation Example 5.

Subsequently,5-(difluoromethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid and CDI (19 mg) was added to anhydrous THF (2 mL), followed bystirring at 80° C. for 1 hour. To the reaction mixture were addedsulfamide (23 mg) and DBU (24 mg) under ice-cooling, followed bystirring at room temperature for about 3 hours. The reaction mixture wasneutralized by the addition of an appropriate amount of ice water and 1M hydrochloric acid, and then extracted with CHCl₃. The organic layerwas washed with brine and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure. The obtained residue was solidifiedwith diisopropyl ether to prepareN-(aminosulfonyl)-5-(difluoromethyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(29 mg).

Example 5

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(50 mg) and 55% sodium hydride (7.2 mg) was added to THF (2 mL),followed by stirring at room temperature for about 115 minutes.Thereafter, to the reaction mixture was added thiophene-2-sulfonylchloride (30 mg) under ice-cooling, followed by further stirring at roomtemperature for about 15 hours. To the reaction mixture was added asaturated aqueous ammonium chloride solution, followed by extractionwith an appropriate amount of ethyl acetate. The organic layer waswashed with brine and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (CHCl₃:MeOH=50:1) to prepare acolorless viscous substance (55 mg). The substance was crystallized froma small amount of diethyl ether to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(2-thienylsulfonyl)-1,3-thiazole-4-carboxamide(41 mg).

Example 6

(2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-4-{[(dimethylamino)sulfonyl]carbamoyl}-1,3-thiazol-5-yl)methylacetate (95 mg) was added to a THF/EtOH (2:1) solution (1.5 mL), andsubsequently, a 1 M aqueous sodium hydroxide solution (0.33 mL) wasadded dropwise thereto under ice-cooling, followed by stirring at roomtemperature for about 20 minutes. To the reaction mixture was added anappropriate amount of a mixed solution of a saturated aqueous ammoniumchloride solution/ice water, including 1 M hydrochloric acid (1.5 mL),followed by extraction with ethyl acetate twice. The organic layer waswashed with brine and dried over MgSO₄, and then the solvent wasevaporated under reduced pressure to prepare colorless syrup (84 mg).The syrup was crystallized from a small amount of ethyl acetate/hexane(1:1) solution and a diethyl ether/diisopropyl ether (1:1) solution,washed again, and collected by filtration to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(dimethylamino)sulfonyl]-5-(hydroxymethyl)-1,3-thiazole-4-carboxamide(71 mg).

Example 7

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylicacid (150 mg) and CDI (78 mg) was added to anhydrous THF (5 mL),followed by heating at 60° C. for about 1 hour. To the reaction mixturewere added N,N-dimethylsulfamide (60 mg) and DBU (73 mg) underice-cooling, respectively, followed by stirring at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and neutralized by the addition of an appropriate amount of purifiedwater and 1 M hydrochloric acid, and then extracted from chloroform. Theobtained organic layer was dried over MgSO₄, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1:2) to obtain2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(dimethylamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide(111 mg) as a white solid.

Example 8

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylicacid (130 mg), benzene sulfonamide (54 mg), DMAP (42 mg), and WSCD HCl(66 mg) were added to methylene chloride (5.2 mL), followed by stirringat room temperature for about 3 days. To the reaction mixture was addedan appropriate amount of CHCl₃ and 0.2 M hydrochloric acid, followed byperforming liquid-separation. The organic layer was washed and dried,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography(CHCl₃:MeOH=50:1) to prepare a white foam. This product was crystallizedfrom ethyl acetate/diethyl ether solution to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(phenylsulfonyl)-1,3-thiazole-4-carboxamide(140 mg).

Example 9

N-(Aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(390 mg) was added to THF (10 mL), followed by cooling to around 0° C.in an ice bath, and subsequently, 55% sodium hydride (38 mg) was addedthereto, followed by stirring at room temperature for about 30 minutes.The reaction mixture was cooled to 0° C. again, and methyl iodide (228mg) was added thereto, followed by stirring at room temperatureovernight. To the reaction mixture were added ice water and hydrochloricacid, followed by extraction with ethyl acetate. The organic layer waswashed with brine and dried over MgSO₄, and then the solvent wasevaporated. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=20:1) to prepareN-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-methyl-1,3-thiazole-4-carboxamide(181 mg).

Example 10

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-hydroxyethyl)(methyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide(150 mg), pyridine (0.1 mL), DMAP (31 mg), and acetyl chloride (100 mg)were sequentially added to methylene chloride (10 mL), followed bystirring at room temperature for about 3 hours. To the reaction mixturewas added a saturated aqueous ammonium chloride solution, followed byextraction with an appropriate amount of ethyl acetate. The organiclayer was washed with brine and dried over MgSO₄, and then the solventwas evaporated. The obtained residue was purified by silica gel columnchromatography (ethyl acetate), and then solidified with diisopropylether to prepare2-[({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)(methyl)amino]ethylacetate (94 mg).

Example 11

N-[(3-{[tert-Butyl(dimethyl)silyl]oxy}pyrrolidin-1-yl)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(580 mg) was added to THF (10 mL), and subsequently, a 1 M TBAF/THFsolution (2.02 mL) was added dropwise thereto, followed by stirring atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, and the obtained residue was neutralized by theaddition of an appropriate amount of 1 M hydrochloric acid, and thenextracted with CHCl₃ several times. The organic layer was washed withbrine and dried over MgSO₄, and then the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=20:1) to obtain2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-1,3-thiazole-4-carboxamide(383 mg) as a white solid.

Example 12

Methylallyl({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)carbamate(66 mg), tetrakis(triphenylphosphine) palladium (0) (20 mg), and1,3-pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg) were added to methylenechloride (5 mL), followed by stirring at room temperature for 2 hours.The mixture was acidified by the addition of 1 M hydrochloric acid, andthen extracted with CHCl₃ several times. The organic layer was washedwith brine and dried over MgSO₄, and then the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (CHCl₃). The isolated purified product thusobtained was solidified with a hexane/ethyl acetate (2:1) solution topreparemethyl({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)carbamate(36 mg).

Example 13

tert-Butyl4-({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)piperidine-1-carboxylate(235 mg) and a 4 M hydrochloric acid/dioxane solution (5 mL) were addedto dioxane (5 mL), followed by stirring at room temperature for 3 hours.The solvent was evaporated under reduced pressure to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(piperazin-1-ylsulfonyl)-1,3-thiazole-4-carboxamidehydrochloride (205 mg).

Example 14

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N4{[(2,2-dimethyl-1,3-dioxan-4-yl)methyl](methyl)amino}sulfonyl)-1,3-thiazole-4-carboxamide(260 mg) was added to THF/purified water (10:1) (2.2 mL), andsubsequently trifluoroacetic acid (2 mL) was added dropwise theretounder ice-cooling, followed by stirring at room temperature for about 1hour. To the reaction mixture was added ice water (20 to 30 g), followedby extraction with an appropriate amount of ethyl acetate twice. Theorganic layer was washed with brine and dried over MgSO₄, and then thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (CHCl₃:MeOH=40:1) toprepare a white foam (210 mg). The obtained white foam was crystallizedfrom a small amount of a hexane/ethyl acetate (1:3) solution, andcollected by filtration while diluting and washing with diethyl ether toprepareN-{[(2,3-dihydroxypropyl)(methyl)amino]sulfonyl}-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(195 mg) as a white powder.

Example 15

BenzylN-({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-(2-fluoroethyl)glycinate(1.22 g) and 10% palladium/carbon (50% wet) (240 mg) were added toacetic acid (35 mL), followed by stirring at a normal temperature/anormal pressure overnight. The catalyst was filtered through Celite, andthe solvent was evaporated under reduced pressure. To the obtainedresidue was added an appropriate amount of ethyl acetate/toluenesolution, and the solvent was evaporated under reduced pressure. Theobtained orange-white foam was purified by silica gel columnchromatography (CHCl₃:MeOH-40:1) to obtain a white foam (0.53 g). Theobtained white foam was crystallized from a warmed ethyl acetate/hexane(1:1) solution (about 10 mL) to prepareN-({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-(2-fluoroethyl)glycine(0.4 g).

Example 16

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(piperazin-1-ylsulfonyl)-1,3-thiazole-4-carboxamidehydrochloride (115 mg) was added to acetonitrile (5 mL), andsubsequently, triethylamine (0.13 mL) and acetyl chloride (15 mg) wereadded thereto, followed by stirring at room temperature for 1 hour. Thesolvent was evaporated under reduced pressure, and the obtained residuewas adjusted to be weakly acidic by the addition of an appropriateamount of purified water and 1 M hydrochloric acid, followed byextraction with an appropriate amount of ethyl acetate. The organiclayer was washed with brine and dried over MgSO₄, and then the solventwas evaporated. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=20:1). The isolated product thus obtained wassolidified with diisopropyl ether to prepareN-[(4-acetylpiperazin-1-yl)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(116 mg).

Example 17

N-[(2-Acetylhydrazino)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(34 mg) was prepared from tert-butyl2-({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)hydrazinecarboxylate(60 mg) by carrying out the same methods as in Example 13 and Example16, successively.

Example 18

N-({[(2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-methylglycine(140 mg), HOBT (38 mg), and WSCD HCl (53 mg) were added to DMF (2 mL),and a 7 M aqueous ammonia/MeOH solution (0.12 mL) was added dropwisethereto, followed by stirring at room temperature for about 13 hours. Tothe reaction mixture was added 0.2 to 0.3 M aqueous hydrochloric acid(20 to 30 mL), followed by extraction with an appropriate amount ofethyl acetate twice. The organic layer was sequentially washed with asaturated aqueous sodium hydrogen carbonate solution and brine, anddried over MgSO₄, and then the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=30:1) to prepare colorless oily substance.The obtained oily substance was crystallized from a small amount ofethyl acetate/hexane (2:1) solution, and collected by filtration whilediluting and washing with diethyl ether to prepareN-{[(2-amino-2-oxoethyl)(methyl)amino]sulfonyl}-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(30 mg).

Example 19

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-({methyl[2-(methylsulfanyl)ethyl]amino}sulfonyl)-1,3-thiazole-4-carboxamide(90 mg) was added to methylene chloride (3 mL), and subsequently,3-chloroperbenzoic acid (37 mg) was added thereto while sufficientlycooling in an MeOH/ice bath, followed by stirring for about 40 minutesunder cooling. To the reaction mixture was added an aqueous sodiumhydrogen carbonate solution, followed by extraction with an appropriateamount of CHCl₃. The organic layer was sequentially washed with asaturated aqueous sodium hydrogen carbonate solution and brine, anddried over MgSO₄, and then the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:2) to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-({methyl[2-(methylsulfinyl)ethyl]amino}sulfonyl)-1,3-thiazole-4-carboxamide (71mg).

Example 20

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-({methyl[2-(methylsulfanyl)ethyl]amino}sulfonyl)-1,3-thiazole-4-carboxamide(100 mg) and 3-chloroperbenzoic acid (93 mg) were added to methylenechloride (3 mL), followed by stirring at room temperature for about 3.5hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution, followed by extraction with an appropriate amount ofCHCl₃. The organic layer was sequentially washed with a saturatedaqueous sodium hydrogen carbonate solution and brine, and dried overMgSO₄, and then the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃:MeOH=100:1) to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-({methyl[2-(methylsulfonyl)ethyl]amino}sulfonyl)-1,3-thiazole-4-carboxamide (86mg).

Example 21

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-1,3-thiazole-4-carboxamide(108 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(91 mg) were added to methylene chloride (5 mL), followed by stirring atroom temperature for 2 hours. To the reaction mixture was added(1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (100 mg),followed by stirring at room temperature for 1 hour. To the reactionmixture was added an appropriate amount of purified water, followed byextraction with CHCl₃. The organic layer was sequentially washed with asaturated aqueous sodium hydrogen carbonate solution and brine, anddried over MgSO₄, and then the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃:MeOH=30:1) to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(3-oxopyrrolidin-1-yl)sulfonyl]-1,3-thiazole-4-carboxamide(117 mg).

Example 22

N-({[(2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)-N-(2-fluoroethyl)glycine(160 mg) and 4-methylmorpholine (27 mg) were added to THF (2.5 mL),followed by cooling to −15 to −10° C. in an MeOH/ice bath under an argonatmosphere. To this mixture was added dropwise isobutyl chloroformate(36 mg), followed by stirring at −15 to −10° C. for about 5 minutes.Further, an aqueous solution (30 to 40 μL) of sodium borohydride (29 mg)was added thereto, followed by stirring at −15 to −10° C. for 15minutes. To the reaction mixture was slowly added an appropriate amountof cooled 0.3 to 0.4 M hydrochloric acid, followed by extraction withethyl acetate. The organic layer was washed with brine and dried overMgSO₄, and then the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃:MeOH=100:1) to prepare colorless oily substance (0.14 g). Theobtained colorless oily substance was crystallized from a small amountof an ethyl acetate/hexane (3:2) solution, and the solid was collectedby filtration while washing with diethyl ether to prepare white solid2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-fluoroethyl)(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide(0.11 g).

Example 23

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (200 mg) and CDI (107 mg) were added to THF (10 mL), followed bystirring at room temperature for 2 hours. To the reaction mixture weresequentially added N-(2-{[tert-butyl (dimethyl)silyl]oxy}ethyl)sulfamide (224 mg) and DBU (134 mg), followed by stirring at roomtemperature overnight. To the reaction mixture were added an appropriateamount of ice water and 1 M hydrochloric acid, followed by extractionwith ethyl acetate. The organic layer was washed with brine and driedover MgSO₄, and then the solvent was evaporated under reduced pressure.The obtained residue was dissolved in THF to give a solution (10 mL),and a 4 M hydrochloric acid/dioxane solution (5 mL) was added to thesolution at 0° C., followed by stirring for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (CHCl₃:MeOH=20:1) toprepare purified product. This purified product was solidified withdiisopropyl ether to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide(127 mg).

Example 24

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxylicacid (600 mg) and CDI (428 mg) were added to THF (20 mL), followed bystirring at room temperature for 2 hours. To the reaction mixture weresequentially added N-{[tert-butyl (dimethyl)silyl]oxy}sulfamide (747 mg)and DBU (502 mg), followed by stirring at room temperature overnight. Tothe reaction mixture were added water and 1 M hydrochloric acid,followed by extraction with ethyl acetate. The organic layer was washedwith brine and dried over MgSO₄, and then the solvent was evaporated.The obtained residue was purified by silica gel column chromatography(ethyl acetate) to prepare N-[({[tert-butyl(dimethyl)silyl]oxy}amino)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(702 mg).

Subsequently, N-[({[tert-butyl(dimethyl)silyl]oxy}amino)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(279 mg) was added to THF (10 mL), and subsequently, 55% sodium hydride(22 mg) was added thereto at 0° C., followed by stirring for 10 minutes.Then, methyl iodide (0.12 g) was added thereto, followed by stirring atroom temperature overnight. To the reaction mixture was added dilutedhydrochloric acid, followed by extraction with CHCl₃. The organic layerwas washed with brine and dried over MgSO₄, and then the solvent wasevaporated. The obtained residue was dissolved in THF (10 mL) to give asolution, a 4 M hydrochloric acid/dioxane solution (5 mL) was added tothe solution at 0° C., followed by stirring at 0° C. for 1 hour, and thesolvent was evaporated. The obtained residue was purified by silica gelcolumn chromatography (CHCl₃:MeOH=20:1), and the purified product wassolidified with diisopropyl ether to prepare2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(hydroxyamino)sulfonyl]-N-methyl-1,3-thiazole-4-carboxamide(106 mg).

Example 168

2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-sulfamoyl-1,3-thiazole-4-carboxamide(100 mg) and acetyl chloride (0.3 mL) were added to acetic acid (3 mL),followed by stirring at about 100° C. for 30 minutes, and acetylchloride (0.3 mL) was added thereto at the same temperature, followed byheating for 30 minutes. The reaction mixture was evaporated underreduced pressure, and ice water was poured into the residue, followed byextraction with an appropriate amount of ethyl acetate. The organiclayer was washed with brine, dried over anhydrous MgSO₄, and evaporatedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (CHCl₃:MeOH=−35:1) to prepareN-(acetylsulfamoyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide(77 mg).

Example 286

N-(Dimethylsulfamoyl)-5-methyl-2-{[(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamidehydrochloride (1:1) (150 mg), a Hunig's base (0.2 mL),(2-fluoro-4-propoxyphenyl) {[2-(trimethylsilyl)ethoxy]methoxy}aceticacid (150 mg), and HATU (160 mg) were sequentially added to acetonitrile(10 mL), followed by stirring at room temperature for 3 hours. Thereaction mixture was evaporated under reduced pressure, and to theresidue were added an appropriate amount of purified water and 1 Mhydrochloric acid, followed by extraction with CHCl₃. The organic layerwas dried and evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane to hexane:ethylacetate=1:3) to obtain a colorless oily substance (240 mg). This oilysubstance was dissolved in dioxane (5 mL), and a 4 M hydrogenchloride/dioxane solution (5 mL) was added thereto, followed by stirringat room temperature for 3 hours. The reaction mixture was evaporatedunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (CHCl₃ to CHCl₃:MeOH=20:1), and theconcentrate was solidified with a hexane-ethyl acetate (5:1) solution toprepareN-(dimethylsulfamoyl)-2-({[(2-fluoro-4-propoxyphenyl)(hydroxy)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide(172 mg) as a white solid.

Example 296

2-[({[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}[3-(2-thienyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxylicacid (150 mg) and CDI (80 mg) were added to THF (6 mL), followed bystirring at 70° C. for 1 hour. The reaction mixture was left to becooled, and then 3-sulfamoylpropylacetate (116 mg) and DBU (144 mg) wereadded thereto, followed by stirring at room temperature overnight. Thereaction mixture was evaporated under reduced pressure, and theresulting residue was purified by silica gel column chromatography (1%AcOH/CHCl₃ to 1% AcOH/CHCl₃:MeOH=20:1) to obtain a colorless oilysubstance. This oily substance was dissolved in a THF/EtOH (1:1)solution (10 mL), and a 1 M aqueous NaOH solution (1 mL) was addedthereto, followed by stirring at room temperature for 3 hours. Thereaction liquid was evaporated under reduced pressure, adjusted to anacidic solution with an appropriate amount of purified water and 1 Mhydrochloric acid, and then extracted with ethyl acetate. The organiclayer was washed with brine and dried over Na₂SO₄, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (CHCl₃ to CHCl₃:MeOH=20:1). Theobtained concentrate was solidified with a hexane-ethyl acetate (2:1)solution to prepareN-[(3-hydroxypropyl)sulfonyl]-2-[({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}[3-(2-thienyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide(105 mg) as a white solid.

Example 298

2-[([3-(5-Chloro-2-thienyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxylicacid (156 mg) and CDI (80 mg) were added to anhydrous THF (10 mL),followed by stirring at 50° C. for 3 hours. The reaction mixture wasleft to be cooled, and then N,N-dimethylsulfamide (80 mg) and DBU (97mg) were sequentially added thereto, followed by stirring at roomtemperature overnight. To the reaction mixture was added an appropriateamount of diluted hydrochloric acid, followed by extraction withchloroform, the aqueous layer was removed, and the solvent wasevaporated. The residue was purified by silica gel column chromatography(CHCl₃:MeOH=20:1), and the obtained colorless oily substance wasdissolved in ethyl acetate (5 mL). A 4 M hydrogen chloride/ethyl acetate(5 mL) was added thereto, followed by stirring for 30 minutes. Thesolvent was evaporated, and to the resulting residue was added anappropriate amount of diisopropyl ether, followed by further stirring.The resulting solid was collected by filtration to prepare2-[([3-(5-chloro-2-thienyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-N-(dimethylsulfamoyl)-5-methyl-1,3-thiazole-4-carboxamidehydrochloride (140 mg) as a white solid.

Example 305

2-[([3-(1-Benzofuran-2-yl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxylicacid (150 mg) and CDI (72 mg) were added to anhydrous THF (5 mL),followed by heating at about 60° C. for 1 hour under an argon gasatmosphere. To the ice-cooled reaction mixture were sequentially addedN,N-dimethylsulfamide (74 mg) and DBU (54 mg), followed by stirring atroom temperature for 3 days. Ice water (about 10 g) including 1 Mhydrochloric acid (0.5 mL) was poured into the reaction solution,followed by extraction with an appropriate amount of ethyl acetateseveral times. The obtained organic layer was washed with brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (CHCl₃:MeOH=200:1) to obtain a colorless syrup(140 mg). This product was dissolved in ethanol (2.5 mL), and a 8 Maqueous potassium hydroxide solution (32 μL) was added dropwise thereto,followed by stirring at room temperature for about 1 hour. The resultingprecipitate was collected by filtration while diluting/washing with asmall amount of ethanol:diethyl ether:diisopropyl ether(1:1:1) solutionto prepare 1-({2-[([3-(1-benzofuran-2-yl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazol-4-yl}carbonyl)-3,3-dimethyldiazathian-1-iodo-2,2-dioxidepotassium salt (93 mg).

Example 308

N-(Dimethylsulfamoyl)-2-[([3-(3-fluorophenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-carboxamide(100 mg) was dissolved in methylene chloride (3 mL), followed byevaporation under reduced pressure, to give an amorphous substance.Ethanol (1 mL) including a 8 M aqueous potassium hydroxide solution (21μL) was poured thereinto, followed by stirring at room temperature forabout 4 hours as it was. The resulting white precipitate was collectedby filtration while washing with a cooled 90% aqueous EtOH solution (2mL) to prepare1-({2-[([3-(3-fluorophenyl)propyl]{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazol-4-yl}carbonyl)-3,3-dimethyldiazathian-1-iodo-2,2-dioxidepotassium salt (33 mg) as a white solid.

The compounds of Examples shown in Tables below were prepared using therespective corresponding starting materials in the same manner as themethods of Examples above. The structures, the preparation methods, andthe physicochemical data for the compounds of Examples are shown inTables below.

TABLE 56 Ex Syn Structure 1 1

2 2

3 3

4 4

5 5

TABLE 57 Ex Syn Structure 6 6

7 7

8 8

9 9

10 10

TABLE 58 Ex Syn Structure 11 11

12 12

13 13

14 14

15 15

TABLE 59 Ex Syn Structure 16 16

17 17

18 18

19 19

20 20

TABLE 60 Ex Syn Structure 21 21

22 22

23 23

24 24

25  1

TABLE 61 Ex Syn Structure 26 1

27 1

28 1

29 1

30 1

TABLE 62 Ex Syn Structure 31 1

32 2

33 2

34 2

35 2

TABLE 63 Ex Syn Structure 36 2

37 2

38 2

39 2

40 2

TABLE 64 Ex Syn Structure 41 2

42 2

43 2

44 2

45 2

TABLE 65 Ex Syn Structure 46 2

47 2

48 2

49 2

50 2

TABLE 66 Ex Syn Structure 51 2

52 2

53 2

54 2

55 2

TABLE 67 Ex Syn Structure 56 2

57 2

58 2

59 2

60 2

TABLE 68 Ex Syn Structure 61 2

62 4

63 4

64 4

65 5

TABLE 69 Ex Syn Structure 66 5

67 5

68 7

69 7

70 7

TABLE 70 Ex Syn Structure 71 7

72 7

73 7

74 7

75 7

TABLE 71 Ex Syn Structure 76 7

77 7

78 7

79 7

80 7

TABLE 72 Ex Syn Structure 81 7

82 7

83 7

84 7

85 7

TABLE 73 Ex Syn Structure 86 7

87 7

88 7

89 7

90 7

TABLE 74 Ex Syn Structure 91 7

92 7

93 7

94 7

95 7

TABLE 75 Ex Syn Structure 96 7

97 7

98 7

99 7

100 7

TABLE 76 Ex Syn Structure 101 7

102 7

103 7

104 7

105 7

TABLE 77 Ex Syn Structure 106 7

107 7

108 7

109 7

110 7

TABLE 78 Ex Syn Structure 111 7

112 7

113 7

114 7

115 7

TABLE 79 Ex Syn Structure 116 7

117 7

118 7

119 7

120 7

TABLE 80 Ex Syn Structure 121 7

122 7

123 7

124 7

125 7

TABLE 81 Ex Syn Structure 126 7

127 7

128 7

129 7

130 7

TABLE 82 Ex Syn Structure 131 7

132 7

133 7

134 7

135 7

TABLE 83 Ex Syn Structure 136 7

137 7

138 7

139 7

140 7

TABLE 84 Ex Syn Structure 141 7

142 7

143 7

144 7

145 7

TABLE 85 Ex Syn Structure 146 7

147 7

148 7

149 7

150 7

TABLE 86 Ex Syn Structure 151 7

152 7

153 7

154 7

155 7

TABLE 87 Ex Syn Structure 156 7

157 7

158 7

159 7

160 7

TABLE 88 Ex Syn Structure 161  7

162  7

163  7

164 10

165 11

TABLE 89 Ex Syn Structure 166  11

167  11

168 168

169  23

170  23

TABLE 90 Ex Syn Structure 171 23

172 23

173 23

174 23

175 23

TABLE 91 Ex Syn Structure 176 23

177 23

178 23

179  1

180  1

TABLE 92 Ex Syn Structure 181 1

182 1

183 1

184 1

185 1

TABLE 93 Ex Syn Structure 186 1

187 1

188 1

189 1

190 1

TABLE 94 Ex Syn Structure 191 1

192 1

193 7

194 7

195 7

TABLE 95 Ex Syn Structure 196 7

197 7

198 7

199 7

200 7

TABLE 96 Ex Syn Structure 201 7

202 7

203 7

204 7

205 7

TABLE 97 Ex Syn Structure 206 7

207 7

208 7

209 7

210 7

TABLE 98 Ex Syn Structure 211 7

212 7

213 7

214 7

215 7

TABLE 99 Ex Syn Structure 216 7

217 7

218 7

219 7

220 7

TABLE 100 Ex Syn Structure 221 7

222 7

223 7

224 7

225 7

TABLE 101 Ex Syn Structure 226 7

227 7

228 7

229 7

230 7

TABLE 102 Ex Syn Structure 231 7

232 7

233 7

234 7

235 7

TABLE 103 Ex Syn Structure 236 7

237 7

238 7

239 7

240 23

TABLE 104 Ex Syn Structure 241 23

242 23

243 23

244 23

245 23

TABLE 105 Ex Syn Structure 246 23

247 23

248 23

249 23

250 23

TABLE 106 Ex Syn Structure 251 23

252 23

253 23

254 23

255 23

TABLE 107 Ex Syn Structure 256 23

257 23

258 23

259 23

260 23

TABLE 108 Ex Syn Structure 261 23

262 23

263 23

264 23

265 23

TABLE 109 Ex Syn Structure 266 23

267 23

268 23

269 23

270 23

TABLE 110 Ex Syn Structure 271 23

272 23

273 23

274 23

275 23

TABLE 111 Ex Syn Structure 276 23

277 23

278 23

279 23

280 23

TABLE 112 Ex Syn Structure 281 23

282 23

283 23

284 23

285 23

TABLE 113 Ex Syn Structure 286 286

287 286

288 286

289 286

290 286

TABLE 114 Ex Syn Structure 291 286

292 286

293 286

294 286

295 286

TABLE 115 Ex Syn Structure 296 296

297 296

298 298

299 298

300 298

TABLE 116 Ex Syn Structure 301 298

302 298

303 298

304 305

305 305

TABLE 117 Ex Syn Structure 306 308

307 308

308 308

TABLE 118 Ex Data 1 NMR-DMSO-d₆: 1.76-1.83 (2H, m), 2.49-2.57 (2H, m),2.12-2.24 (4H, m), 2.62-2.71 (5H, m), 2.86 (6H, s), 2.95-2.99 (2H, m),3.71-3.74 (3H, m), 4.39-4.64 (2H, m), 6.86-6.95 (4H, m), 7.14-7.25 (5H,m), 10.75 (1H, br). [ESI+]: 585 2 [ESI+]: 575 3 [EI+]: 604 4 [FAB+]: 5835 [FAB+]: 600 6 [ESI+]: 591 7 NMR-DMSO-d₆: 1.87 (2H, br), 2.00 (3H, s),2.30-2.50 (2H, m), 2.69 (3H, s), 2.87 (6H, s), 3.31-3.50 (2H, m), 3.75(6H, s), 4.60-4.90 (2H, m), 6.55-7.30 (7H, m), 10.90 (1H, s). [ESI+]:575 8 [ESI+]: 594 9 [ESI+]: 547 10 [ESI+]: 632 11 NMR-DMSO-d₆: 1.80-2.05(7H, m), 2.30-2.65 (2H, m), 3.16-3.60 (7H, m), 3.75 (6H, s), 4.29 (1H,s), 4.70-5.20 (2H, m), 6.45-7.45 (7H, m), 8.55 (1H, s), 11.40 (1H, s).[ESI+]: 603 12 NMR-DMSO-d₆: 1.77-2.05 (5H, m), 2.30-2.62 (2H, m),3.20-3.60 (5H, m), 3.74 (6H, s), 4.61-4.99 (2H, m), 6.48-6.80 (2H, m),6.95-7.72 (6H, m), 7.95 (1H, s). [ESI+]: 591 13 NMR-DMSO-d₆: 1.81-2.03(5H, m), 2.30-2.68 (2H, m), 3.15-3.60 (10H, m), 3.75 (6H, s), 4.74-5.02(2H, m), 6.51-6.76 (2H, m), 6.92-7.31 (5H, m), 8.61 (1H, s), 9.04-9.34(2H, m), 11.94 (1H, brs). [ESI+]: 602 14 [EI+]: 620 15 [FAB+]: 637 16[ESI+]: 644 17 [ESI+]: 590 18 [FAB+]: 604

TABLE 119 Ex Data 19 [FAB+]: 637 20 [FAB+]: 653 21 NMR-DMSO-d₆:1.80-2.05 (5H, m), 2.30-2.70 (4H, m), 3.20-4.00 (12H, m), 4.71-5.03 (2H,m), 6.45-7.40 (7H, m), 8.62 (1H, s), 11.83 (1H, brs). [ESI+]: 601 22[FAB+]: 623 23 NMR-DMSO-d₆: 1.87 (2H, br), 2.00 (3H, s), 2.31 (2H, br),3.02 (2H, br), 3.38-3.53 (4H, m), 3.75 (6H, s), 4.80-4.93 (2H, m), 6.59(2H, br), 6.91-7.27 (5H, m), 7.72 (1H, s), 8.54 (1H, s), 11.5 (1H, s).[ESI+]: 577 24 NMR-DMSO-d₆: 1.87 (2H, br), 2.00 (3H, s), 2.42 (2H, br),3.05 (3H, s), 3.39 (2H, br), 3.74 (6H, s), 4.92 (2H, br), 6.61 (2H, br),7.02-7.18 (5H, m), 8.61 (1H, s), 10.4 (1H, br). [ESI+]: 563 25 [FAB+]:603 26 NMR-DMSO-d₆: 1.45-1.53 (2H, m), 2.16-2.22 (2H, m), 2.69 (3H, s),2.86 (6H, s), 3.30 (2H, br), 3.65-3.82 (6H, m), 4.75 (2H, s), 6.60-6.65(2H, m), 6.97-7.46 (6H, m), 10.81 (1H, br). [ESI+]: 611 27 NMR-DMSO-d₆:1.30-1.80 (2H, m), 2.34-2.40 (2H, m), 2.65-2.66 (3H, m), 2.86-2.87 (6H,m), 3.30-3.38 (2H, m), 3.74-3.76 (3H, m), 4.66-4.86 (2H, m), 5.50-5.58(1H, m), 5.66-5.86 (1H, m), 6.70-6.85 (2H, m), 7.03-7.32 (6H, m), 10.81(1H, br). [ESI+]: 579 28 NMR-DMSO-d₆: 1.40-1.80 (2H, m), 2.38-2.43 (2H,m), 2.64-2.65 (3H, m), 2.86-2.88 (6H, m), 3.30-3.42 (2H, m), 3.81-3.84(3H, m), 4.64-4.89 (2H, m), 5.38-5.50 (1H, m), 5.76-5.97 (1H, m),6.76-6.82 (1H, m), 7.07-7.28 (5H, m), 7.57-7.66 (1H, m), 8.11 (1H, s),10.76 (1H, br). [ESI+]: 562 mp: 178-179° C. 29 NMR-DMSO-d₆: 0.99-1.80(6H, m), 2.20-2.24 (2H, m), 2.66 (3H, s), 2.86 (6H, s), 3.35-3.39 (2H,m), 4.65-4.80 (2H, m), 6.70-6.72 (2H, m), 6.97-7.25 (7H, m), 9.36 (1H,s), 10.82 (1H, s). [ESI+]: 557

TABLE 120 Ex Data 30 NMR-DMSO-d₆: 1.04-1.74 (6H, m), 2.20-2.25 (2H, m),2.67 (3H, s), 2.87 (6H, s), 3.32-3.38 (2H, m), 4.19 (2H, dt, J = 30.2Hz, 3.5 Hz), 4.67-4.79 (4H, m), 6.91-7.23 (9H, m), 10.82 (1H, br).[ESI+]: 603 31 NMR-DMSO-d₆: 1.25-1.48 (6H, m), 2.18-2.22 (2H, m), 2.68(3H, s), 2.87 (6H, s), 3.30-3.37 (2H, m), 3.76-3.80 (3H, m), 4.73-4.78(2H, m), 6.92-7.36 (7H, m), 8.12-8.21 (1H, m), 10.85 (1H, br). [ESI+]:572 mp: 125-126° C. 32 [ESI+]: 533 33 [ESI+]: 515 34 [ESI+]: 561 35[ESI+]: 549 36 [ESI+]: 625, 627 37 [ESI+]: 567, 569 38 [ESI+]: 577 39[ESI+]: 521 40 [ESI+]: 566, 568 41 [ESI+]: 549 42 [ESI+]: 579 43 [ESI+]:563 44 [ESI+]: 556 45 [ESI+]: 555 46 [ESI+]: 572, 574 47 [ESI+]: 527 48[ESI+]: 558 49 [ESI+]: 561 50 [ESI+]: 589 51 [ESI+]: 599 52 [ESI+]: 59353 [ESI+]: 561 54 [ESI+]: 543 55 [ESI+]: 545 56 [ESI+]: 571

TABLE 121 Ex Data 57 [ESI+]: 598 58 [ESI+]: 621 59 [ESI+]: 607 60[ESI+]: 573 61 [ESI+]: 587 62 NMR-DMSO-d₆: 1.80-2.03 (5H, m), 2.40-2.58(2H, m), 3.41 (2H, br), 3.71-3.77 (6H, m), 4.55-4.82 (2H, m), 6.62-7.26(7H, m), 7.71 (2H, br), 7.99 (1H, s), 12.12 (1H, br). [ESI+]: 533 mp:173-175° C. 63 NMR-DMSO-d₆: 1.79-2.04 (5H, m), 2.34-2.62 (5H, m),3.26-3.45 (2H, m), 3.69-3.80 (6H, m), 4.51-4.86 (2H, m), 6.57-7.31 (7H,m), 7.78 (1H, s), 8.00 (1H, s), 12.14 (1H, brs). [FAB+]: 547 64NMR-DMSO-d₆: 1.80-2.04 (5H, m), 2.36-2.64 (2H, m), 3.29-3.49 (2H, m),3.75 (6H, s), 4.63-4.91 (2H, m), 6.59 (2H, s), 6.93 (1H, s), 7.00-7.30(5H, m), 7.73 (2H, s), 12.27 (1H, s). [ESI+]: 517 65 [FAB+]: 629 66[ESI+]: 598 67 [FAB+]: 613 68 NMR-DMSO-d₆: 1.82-1.92 (2H, br), 2.01 (3H,s), 2.32-2.45 (2H, m), 2.88 (6H, s), 3.30-3.48 (2H, m), 3.75 (6H, s),4.72-5.00 (2H, br), 6.54-6.74 (2H, br), 6.96-7.28 (5H, m), 8.57 (1H, s),11.50 (1H, s) [ESI+]: 561 69 NMR-DMSO-d₆: 1.82-1.92 (2H, br), 2.00 (3H,s), 2.30-2.55 (2H, m), 3.30-3.50 (2H, m), 3.75 (6H, s), 4.70-5.00 (2H,m), 6.52-6.72 (2H, m), 6.94-7.28 (5H, m), 7.57 (2H, s), 8.52 (1H, s),11.36 (1H, s). [FAB+]: 533 mp: 147-150° C. 70 NMR-DMSO-d₆: 1.87 (2H,br), 2.01 (3H, s), 2.40 (2H, br), 2.54 (3H, d, J = 4.7 Hz), 3.3-3.45(2H, m), 3.75 (6H, s), 4.80-5.01 (2H, m), 6.55-6.80 (2H, m), 6.93-7.25(5H, m), 7.67 (1H, d, J = 4.77), 8.56 (1H, s), 11.4 (1H, s). [ESI+]: 547

TABLE 122 Ex Data 71 NMR-DMSO-d₆: 1.06 (3H, t, J = 7.2), 1.87 (2H, br),2.01 (3H, s), 2.41 (2H, br), 2.94-3.00 (2H, m), 3.40 (2H, br), 3.75 (6H,s), 4.92 (2H, br), 6.61 (2H, br), 6.91-7.37 (5H, m), 7.82 (1H, br), 8.55(1H, s), 11.3 (1H, s). [ESI+]: 561 mp: 143-144° C. 72 NMR-DMSO-d₆: 0.82(3H, t, J = 7.4), 1.42-1.51 (2H, m), 1.87 (2H, br), 2.00 (3H, s), 2.41(2H, br), 2.89 (2H, m), 3.40 (2H, br), 3.74 (6H, s), 4.92 (2H, br), 6.62(2H, br), 6.95-7.31 (5H, m), 7.82 (1H, br), 8.53 (1H, s), 11.3 (1H, s).[ESI+]: 575 73 NMR-DMSO-d₆: 1.05-1.11 (6H, m), 1.86 (2H, br), 2.00 (3H,s), 2.39 (2H, br), 3.31-3.41 (1H, m), 3.44-3.54 (2H, m), 3.75 (6H, s),4.80-4.92 (2H, m), 6.57-6.72 (2H, m), 6.99-7.20 (5H, m), 7.84 (1H, br),8.54 (1H, s), 11.3 (1H, s). [ESI+]: 575 74 NMR-DMSO-d₆: 1.87 (2H, br),2.00 (3H, s), 2.39 (2H, br), 3.08-3.15 (2H, m), 3.17 (3H, s), 3.36-3.45(4H, m), 3.74 (6H, s), 4.80-4.95 (2H, m), 6.57-6.65 (2H, m), 7.00-7.17(5H, m), 7.87 (1H, br), 8.54 (1H, s), 11.4 (1H, s). [ESI+]: 591 ( ) 75NMR-DMSO-d₆: 1.64-1.72 (2H, m), 1.87 (2H, br), 2.00 (3H, s), 2.34 (2H,br), 2.95-2.99 (2H, m), 3.16 (3H, s), 3.27-3.42 (4H, m), 3.75 (6H, s),4.77-4.92 (2H, m), 6.61 (2H, br), 7.01-7.17 (5H, m), 7.86 (1H, br), 8.55(1H, s), 11.4 (1H, s). [FAB+]: 605 76 NMR-DMSO-d₆: 0.53 (4H, m), 1.86(2H, br), 2.00 (3H, s), 2.26-2.51 (3H, m), 3.23-3.50 (2H, m), 3.75 (6H,s), 4.80-4.93 (2H, m), 6.59-6.72 (2H, m), 6.99-7.15 (5H, m), 8.22 (1H,br), 8.57 (1H, s), 11.5 (1H, s). [ESI+]: 573 77 NMR-DMSO-d₆: 1.50 (2H,m), 1.85-2.05 (9H, m), 2.38 (2H, br), 3.78 (2H, br), 3.75 (7H, br),4.81-4.94 (2H, m), 6.58 (2H, br), 6.98-7.14 (5H, m), 8.26 (1H, br), 8.53(1H, s), 11.4 (1H, s). [ESI+]: 587 78 NMR-DMSO-d₆: 1.85 (2H, br), 2.04(3H, s), 2.37 (2H, br), 3.32 (2H, br), 3.74 (6H, s), 4.76-4.90 (2H, m),6.57 (2H, br), 6.95-7.29 (11H, m), 8.48 (1H, s), 10.6 (1H, br), 12.0(1H, s). [FAB+]: 609

TABLE 123 Ex Data 79 NMR-DMSO-d₆: 1.80-2.05 (5H, m), 2.30-2.65 (2H, m),3.20-3.50 (2H, m), 3.74 (6H, s), 4.57-4.99 (2H, m), 6.40-7.55 (9H, m),7.74-8.10 (2H, m), 8.47 (1H, s). [ESI+]: 610 80 NMR-DMSO-d₆: 1.88 (2H,br), 2.00 (3H, s), 2.41 (2H, br), 3.37 (2H, br), 3.75 (6H, s), 4.17 (2H,d, J = 5.7 Hz), 4.80-4.99 (2H, m), 6.55-6.78 (2H, m), 7.14-7.32 (11H,m), 8.47 (1H, s), 11.4 (1H, s). [FAB+]: 623 81 NMR-DMSO-d₆: 1.86 (2H,br), 2.00 (3H, s), 2.36 (2H, br), 3.14-3.19 (2H, m), 3.29 (2H, br), 3.50(2H, m), 3.73 (6H, s), 4.43 (3H, s), 4.89 (2H, br), 6.60 (2H, br),7.03-7.34 (10H, m), 7.89 (1H, br), 8.52 (1H, s), 11.4 (1H, s). [ESI+]:667 82 NMR-DMSO-d₆: 1.79-1.83 (4H, m), 1.83 (2H, br), 2.00 (3H, s), 2.34(2H, br), 3.31-3.43 (5H, m), 3.75 (6H, s), 4.78-4.93 (2H, m), 6.59-6.70(2H, m), 7.00-7.15 (5H, m), 8.57 (1H, s), 11.4 (1H, s). [FAB+]: 587 83NMR-DMSO-d₆: 1.26 (3H, s), 1.70-2.10 (7H, m), 2.30-2.50 (2H, m),3.20-3.80 (12H, m), 4.75-5.10 (3H, m), 6.55-7.30 (7H, m), 8.31 (1H, s),11.36 (1H, s). [ESI+]: 617 84 NMR-DMSO-d₆: 1.37-1.50 (2H, m), 1.68-2.05(7H, m), 2.30-2.75 (2H, m), 3.04-3.56 (10H, m), 3.75 (6H, s), 4.70-5.00(2H, m), 6.50-7.33 (7H, m), 8.52 (1H, s), 11.51 (1H, s). [ESI+]: 631 85NMR-DMSO-d₆: 1.79-2.05 (5H, m), 2.30-2.75 (6H, m), 3.20-3.60 (6H, m),3.75 (6H, s), 4.70-5.00 (2H, m), 6.50-7.33 (7H, m), 8.51 (1H, s), 11.73(1H, s). [ESI+]: 619 86 NMR-DMSO-d₆: 1.79-2.05 (5H, m), 2.30-2.70 (2H,m), 3.20-3.60 (6H, m), 3.75-3.80 (10H, m), 4.70-5.05 (2H, m), 6.45-7.40(7H, m), 8.60 (1H, s), 12.00 (1H, brs). [ESI+]: 651 87 NMR-DMSO-d₆:1.80-2.05 (5H, m), 2.30-2.75 (2H, m), 3.18-3.60 (6H, m), 3.75 (6H, s),3.90 (2H, s), 4.70-5.00 (2H, m), 6.50-7.33 (7H, m), 8.09 (1H, s), 8.58(1H, s), 11.87 (1H, brs). [ESI+]: 616

TABLE 124 Ex Data 88 NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.41 (2H,br), 3.20 (6H, s), 3.33-3.52 (10H, m), 3.74 (6H, s), 4.91 (2H, br), 6.59(2H, br), 6.94-7.28 (5H, m), 8.53 (1H, s), 11.4 (1H, s). [ESI+]: 649 891.82-1.95 (2H, br), 2.00 (3H, s), 2.31-2.62 (2H, m), 3.30-3.60 (5H, m),3.70-3.78 (9H, m), 4.91 (2H, br), 6.61 (2H, br), 6.95-7.27 (5H, m), 7.61(1H, s), 8.64 (1H, s). [ESI+]: 605 mp: 135-137° C. 90 NMR-DMSO-d₆:1.83-2.04 (5H, m), 2.30-2.67 (2H, m), 3.20-3.60 (2H, m), 3.71 (3H, s),3.75 (6H, s), 4.81-5.00 (2H, m), 5.03 (2H, s), 6.54-6.76 (2H, m),6.95-7.44 (10H, m), 8.63 (1H, s). [ESI+]: 681 91 NMR-DMSO-d₆: 1.81-2.03(5H, m), 2.31-2.65 (2H, m), 3.20-3.60 (9H, m), 3.65-3.80 (9H, m),4.70-5.00 (2H, m), 6.50-6.78 (2H, m), 6.91-7.31 (5H, m), 8.54 (1H, s).[ESI+]: 649 92 NMR-DMSO-d₆: 1.80-2.05 (5H, m), 2.20-2.70 (2H, m),3.20-3.50 (4H, m), 3.62-3.80 (9H, m), 3.99-4.12 (2H, m), 4.36-4.55 (2H,m), 4.72-4.97 (3H, m), 6.51-6.74 (2H, m), 6.92-7.29 (5H, m), 8.46 (1H,s). [ESI+]: 661 93 NMR-DMSO-d₆: 1.87 (2H, br), 2.00 (3H, s), 2.29-2.65(2H, m), 3.20-3.50 (2H, m), 3.67-3.80 (9H, m), 4.41 (2H, d, J = 5.0),4.75-4.97 (2H, m), 5.14-5.25 (2H, m), 5.88-6.00 (1H, m), 6.52-6.73 (2H,m), 6.93-7.32 (5H, m), 8.59 (1H, s). [ESI+]: 631 94 [ESI+]: 702 95[ESI+]: 648 96 [ESI+]: 634 [EI-MS] 97 [ESI+]: 618 98 [FAB+]: 621

TABLE 125 Ex Data 99 NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.10 (3H,s), 2.30-2.68 (2H, m), 2.94 (3H, s), 3.17-3.50 (5H, m), 3.75 (6H, s),4.72-5.04 (2H, m), 6.49-6.76 (2H, m), 6.91-7.29 (5H, m), 8.58 (1H, s).[ESI+]: 618 100 NMR-DMSO-d₆: 1.80-2.05 (5H, m), 2.30-2.60 (2H, m), 2.70(3H, s), 2.92 (3H, s), 3.23-3.50 (2H, m), 3.65 (2H, dt, 27.3 Hz, 5.0Hz), 3.75 (6H, s), 4.57 (2H, dt, 47.4 Hz, 5.0 Hz), 4.70-4.93 (2H, m),6.50-7.35 (7H, m), 11.40 (1H, brs). [ESI+]: 607 101 NMR-DMSO-d₆:1.80-2.05 (5H, m), 2.30-2.60 (2H, m), 2.70 (3H, s), 2.94 (3H, s),3.22-3.50 (2H, m), 3.68-3.83 (8H, m), 4.70-4.93 (2H, m), 6.20 (1H, dt,3.8 Hz, 55.3 Hz), 6.50-7.35 (7H, m), 11.35 (1H, s). [ESI+]: 625 102NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.12 (2H, br), 2.39 (2H, br),2.85 (3H, s), 3.40 (2H, br), 3.48-3.55 (2H, m), 3.64 (2H, br), 3.75 (6H,s), 3.84-3.89 (1H, m), 4.63 (1H, br), 4.91 (1H, br), 6.61 (2H, m),7.01-7.19 (5H, m), 8.54 (1H, s), 11.6 (1H, s). [ESI+]: 617 103 [ESI+]:660 104 NMR-DMSO-d₆: 1.88 (2H, br), 2.01 (3H, s), 2.35 (2H, br), 2.71(3H, s), 3.40 (2H, br), 3.70 (3H, s), 3.75 (6H, s), 4.84 (2H, br), 6.60(2H, br), 7.02-7.19 (5H, m), 10.3 (1H, s), 11.3 (1H, br). [ESI+]: 577105 NMR-DMSO-d₆: 1.80-2.10 (5H, m), 2.30-2.60 (2H, m), 2.70 (3H, s),2.92 (3H, s), 3.30-3.50 (4H, m), 3.58-3.80 (10H, m), 4.50 (2H, dt, J =4.0, 48.0 Hz), 4.82 (2H, br), 6.60 (2H, br), 6.90-7.34 (5H, m), 10.90(1H, brs). [ESI+]: 651 106 1.88 (2H, br), 2.00 (3H, s), 2.41 (2H, br),2.70 (3H, s), 3.36 (2H, br), 3.76 (6H, s), 4.12-4.22 (2H, m), 4.29-4.33(2H, m), 4.85 (2H, br), 5.26-5.40 (1H, m), 6.60 (2H, br), 7.01-7.19 (5H,m). [ESI+]: 605 107 [ESI+]: 727

TABLE 126 Ex Data 108 NMR-DMSO-d₆: 1.87 (2H, br), 2.01 (3H, s),2.31-2.52 (2H, m), 3.20-3.39 (5H, m), 3.75 (6H, s), 4.92 (2H, br), 6.58(2H, s), 6.95-7.29 (5H, m), 8.58 (1H, s), 11.86 (1H, br). [FAB+]: 532mp: 133-134° C. 109 NMR-DMSO-d₆: 1.88 (2H, br), 2.01 (3H, s), 2.30-2.45(2H, m), 2.71 (3H, s), 3.28-3.37 (5H, m), 3.75 (6H, s), 4.83 (2H, br),6.59 (2H, s), 7.01-7.20 (5H, m), 11.18 (1H, br). [FAB+]: 546 mp:128-131° C. 110 NMR-DMSO-d₆: 1.89 (2H, br), 2.00 (3H, s), 2.54-2.82 (2H,m), 3.35-3.50 (2H, m), 3.76 (6H, brs), 4.72-4.98 (2H, m), 6.47-6.97 (4H,m), 7.61 (2H, s), 8.51 (1H, s), 11.34 (1H, br). [FAB+]: 573, 575 mp:154-156° C. 111 1.87 (2H, br), 2.00 (3H, s), 2.11 (3H, brs), 2.40 (2H,br), 3.38 (2H, br), 3.76 (6H, brs), 4.91 (2H, br), 5.71-5.99 (2H, m),6.61 (2H, br), 7.61 (2H, s), 8.54 (1H, s), 11.34 (1H, br). [ESI+]: 537112 [ESI+]: 569 113 NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.40-2.54(2H, m), 3.23-3.49 (2H, m), 3.75 (6H, s), 4.93 (2H, br), 6.55 (2H, br),6.93-7.29 (4H, m), 7.61 (2H, s), 8.53 (1H, s), 11.33 (1H, s). [FAB+]:551 mp: 145-146° C. 114 [FAB+]: 569 115 [FAB+]: 569 116 [FAB+]: 551 117NMR-DMSO-d₆: 1.78 (2H, br), 2.00 (3H, s), 2.67 (2H, br), 3.56 (2H, br),3.74 (6H, s), 4.76-5.00 (2H, m), 6.46-6.76 (2H, m), 7.03-7.20 (2H, m),7.34 (1H, br), 7.62 (2H, s), 8.54 (1H, s), 11.4 (1H, s). [ESI+]: 585 118[FAB+]: 558

TABLE 127 Ex Data 119 NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.45(2H, br), 2.87 (6H, s), 3.39 (2H, br), 3.74 (6H, s), 4.91 (2H, br), 6.57(2H, br), 7.04-7.18 (4H, m), 8.55 (1H, s), 11.4 (1H, s). [ESI+]: 579 mp:128-131° C. 120 [ESI+]: 564 121 NMR-DMSO-d₆: 1.80-2.03 (5H, m),2.39-2.63 (2H, m), 3.27-3.53 (2H, m), 3.74 (6H, s), 4.56-4.86 (2H, m),6.53-6.71 (2H, m), 7.01-7.30 (5H, m), 7.57 (2H, s), 8.80 (1H, s), 11.64(1H, s). [ESI+]: 517 mp: 136-141° C. 122 NMR-DMSO-d₆: 1.81-2.02 (5H, m),2.34-2.64 (2H, m), 3.14-3.45 (2H, m), 3.74 (6H, s), 4.56-4.83 (2H, m),6.54 (2H, s), 6.95-7.29 (5H, m), 7.46-7.57 (3H, m), 8.36 (1H, s), 11.69(1H, s). [ESI+]: 532 123 NMR-DMSO-d₆: 1.74-1.86 (2H, m), 2.00 (3H, s),2.35-2.59 (2H, m), 3.18-3.41 (2H, m), 3.76 (6H, s), 4.44-4.77 (2H, m),6.51-6.76 (3H, m), 6.97-7.30 (5H, m), 7.45-7.58 (3H, m), 11.77 (1H, s).[ESI+]: 516 124 NMR-DMSO-d₆: 1.73-2.03 (5H, m), 2.29-2.62 (2H, m),3.09-3.42 (2H, m), 3.64-3.80 (6H, m), 4.34-4.68 (2H, m), 6.10 (1H, s),6.57 (2H, s), 6.94-7.41 (9H, m), 11.34 (1H, s). [FAB+]: 515 125 [ESI+]:633 126 NMR-DMSO-d₆: 1.76-1.83 (2H, m), 2.49-2.57 (2H, m), 2.66-2.69(3H, m), 2.87 (6H, s), 3.37-3.56 (4H, m), 3.70-3.74 (6H, m), 4.68-4.87(2H, m), 6.45-6.53 (2H, m), 7.02-7.27 (6H, m), 10.78 (1H, br). [ESI+]:575 mp: 132-135° C. 127 NMR-DMSO-d₆: 1.77-1.85 (2H, m), 2.00 (3H, s),2.35-2.60 (2H, m), 3.20-3.40 (5H, m), 3.77 (6H, s), 4.49-4.73 (2H, m),6.59-7.52 (9H, m), 12.13 (1H, br). [ESI+]: 515 128 [ESI+]: 547 129[ESI+]: 559

TABLE 128 Ex Data 130 [ESI+]: 545 131 NMR-DMSO-d₆: 0.75 (2H, br), 0.97(2H, br), 1.87 (3H, brs), 2.46 (2H, br), 3.23-3.45 (2H, m), 3.71 (6H,s), 4.92 (2H, br), 6.57 (2H, br), 6.94-7.31 (5H, m), 7.60 (2H, s), 8.53(1H, s), 11.33 (1H, br). [FAB+]: 559 mp: 147-149° C. 132 [FAB+]: 599 1331.02 (2H, br), 1.21 (2H, br), 1.34 (2H, br), 2.23 (2H, br), 2.69 (3H,s), 3.35 (2H, br), 3.73 (3H, s), 4.66 (2H, br), 6.87-7.26 (9H, m), 7.58(2H, br), 10.6 (1H, s). [ESI+]: 543 134 NMR-DMSO-d₆: 1.85 (2H, br), 2.39(2H, br), 2.71 (3H, s), 3.43 (2H, br), 3.67 (3H, s), 3.75 (6H, s),4.70-4.85 (2H, m), 6.48-6.56 (2H, m), 6.93-7.19 (5H, m), 10.3 (1H, s),11.4 (1H, br). [ESI+]: 563 135 NMR-DMSO-d₆: 1.82-1.95 (5H, m), 2.35-2.55(5H, m), 2.71 (3H, s), 3.26-3.51 (2H, m), 3.71 (6H, s), 4.67-4.91 (3H,m), 5.21 (1H, s), 6.53-6.74 (2H, m), 6.96-7.28 (5H, m), 7.64 (1H, brs),10.82 (1H, s). [ESI+]: 587 136 NMR-DMSO-d₆: 1.84 (2H, br), 2.00 (3H, s),2.21 (3H, s), 2.32 (2H, br), 2.54 (3H, d, J = 4.4 Hz), 3.32-3.45 (2H,m), 3.75 (6H, s), 4.79-4.93 (2H, m), 6.58-7.11 (6H, m), 7.64 (1H, br),8.56 (1H, s), 11.4 (1H, s). [FAB+]: 561 137 NMR-DMSO-d₆: 1.88 (2H, br),2.01 (3H, s), 2.41-2.55 (5H, m), 3.36 (2H, br), 3.76 (6H, s), 4.81-4.93(2H, m), 6.60-7.66 (5H, m), 8.55 (1H, s), 11.4 (1H, s). [ESI+]: 553 138[ESI+]: 580 139 NMR-DMSO-d₆: 1.86 (2H, br), 1.99 (3H, s), 2.39 (2H, br),2.53 (3H, br), 3.32 (2H, br), 3.74 (6H, s), 4.77-4.99 (2H, m), 6.50-7.00(5H, m), 7.64 (1H, br), 8.56 (1H, s), 11.4 (1H, s). [ESI+]: 583 140NMR-DMSO-d₆: 1.86 (2H, br), 2.00 (3H, s), 2.33 (3H, s), 2.39 (2H, br),2.54-2.75 (4H, m), 3.40 (2H, br), 3.76 (6H, s), 4.77-4.98 (2H, m),6.35-6.74 (4H, m), 7.65 (1H, br), 8.56 (1H, s), 11.4 (1H, s). [ESI+]:567

TABLE 129 Ex Data 141 NMR-DMSO-d₆: 1.03-1.08 (2H, m), 1.85 (2H, br),2.00 (3H, s), 2.42 (2H, br), 2.71 (3H, m), 2.94-3.01 (2H, m), 3.48 (2H,br), 3.75 (6H, s), 4.83 (2H, br), 6.56 (2H, br), 6.97-7.22 (5H, m), 7.79(1H, br), 10.8 (1H, s). [ESI+]: 593 142 NMR-DMSO-d₆: 1.82 (2H, br), 2.00(3H, s), 2.49-2.55 (8H, m), 3.44 (2H, br), 3.75 (6H, s), 4.90 (2H, br),6.55-6.80 (3H, m), 7.12 (1H, br), 7.63 (1H, br), 8.55 (1H, s), 11.3 (1H,s). [ESI+]: 567 143 [ESI+]: 591, 593 144 NMR-DMSO-d₆: 1.80-1.92 (2H, m),2.30-2.67 (2H, m), 3.26-3.54 (2H, m), 3.75 (6H, s), 4.64-4.95 (2H, m),6.45-6.75 (3H, m), 6.89-7.36 (5H, m), 7.67 (2H, s), 11.32 (1H, s).[ESI+]: 553 145 NMR-DMSO-d₆: 1.86 (2H, br), 2.32-2.60 (5H, m), 3.22-3.54(2H, m), 3.75 (6H, s), 4.68-4.93 (2H, m), 6.45-6.62 (3H, m), 6.92-7.34(5H, m), 11.76 (1H, br). [FAB+]: 552 mp: 113-114° C. 146 NMR-DMSO-d₆:1.78-2.04 (5H, m), 2.34-2.65 (5H, m), 3.24-3.50 (2H, m), 3.55-3.82 (6H,m), 4.61-4.91 (2H, m), 6.61-6.63 (2H, m), 6.93-7.28 (5H, m), 7.59-8.09(4H, m), 11.07 (1H, s). [FAB+]: 541 147 [FAB+]: 537 148 NMR-DMSO-d₆:1.75-1.84 (2H, m), 2.00 (3H, s), 2.34-2.59 (5H, m), 3.21-3.42 (2H, m),3.76 (6H, s), 4.43-4.78 (2H, m), 6.51-6.78 (3H, m), 6.95-7.31 (5H, m),7.50 (1H, s), 7.63 (1H, d, J = 4.7 Hz), 11.72 (1H, s). [FAB+]: 541 149[ESI+]: 575 150 [ESI+]: 573 151 [ESI+]: 573 152 [ESI+]: 591

TABLE 130 Ex Data 153 NMR-DMSO-d₆: 0.96-1.07 (5H, m), 1.88 (2H, br),2.40 (2H, br), 2.47-2.64 (2H, m), 2.71 (3H, s), 3.29-3.50 (2H, m), 3.75(6H, s), 4.61-4.92 (2H, m), 6.53-6.72 (2H, m), 6.92-7.32 (6H, m), 7.67(1H, br), 10.83 (1H, br). [ESI+]: 575 mp: 162-164° C. 154 NMR-DMSO-d₆:1.85 (2H, br), 2.38 (2H, br), 2.44-2.63 (2H, m), 2.71 (3H, s), 3.22-3.50(2H, m), 3.75 (6H, s), 4.60-4.93 (2H, m), 6.42-6.62 (2H, m), 6.91-7.29(7H, m), 7.63 (1H, br), 10.83 (1H, brs). [ESI+]: 587 mp: 112-113° C. 155NMR-DMSO-d₆: 1.03-1.07 (3H, m), 1.85 (2H, br), 2.40-2.62 (2H, m), 2.71(3H, br), 2.97 (3H, br), 3.29-3.48 (2H, m), 3.81 (6H, s), 4.67 (1H, br),4.87 (2H, br), 6.66 (2H, br), 6.82-7.28 (5H, m), 7.77 (1H, br), 10.8(1H, s). [ESI+]: 611 156 NMR-DMSO-d₆: 0.69-1.01 (4H, m), 1.82-1.92 (3H,m), 2.32-2.58 (5H, m), 2.71 (3H, s), 3.28-3.49 (2H, m), 3.71 (6H, s),4.60-4.93 (2H, m), 6.46-6.72 (2H, m), 6.90-7.29 (5H, m), 7.64 (1H, brs),10.81 (1H, s). [ESI+]: 587 157 [ESI+]: 613 158 [FAB+]: 673 159 [ESI+]:575 160 NMR-DMSO-d₆: 1.03 (2H, br), 1.22 (2H, br), 1.34 (2H, br), 2.23(2H, br), 2.54 (3H, s), 2.68 (3H, s), 3.37 (2H, br), 3.73 (3H, s), 4.66(2H, br), 6.87-7.25 (8H, m), 7.64 (1H, br), 10.7 (1H, s). [FAB+]: 557161 NMR-DMSO-d₆: 1.88 (2H, br), 2.40 (2H, br), 2.71 (3H, s), 3.20 (3H,s), 3.49 (2H, br), 3.67 (3H, s), 3.76 (6H, s), 4.38 (2H, s), 4.70-4.87(2H, m), 6.61-6.75 (2H, m), 7.00-7.18 (5H, m), 10.35 (1H, s). [FAB+]:607 mp: 151-153° C. 162 [FAB+]: 601 163 [FAB+]: 595

TABLE 131 Ex Data 164 NMR-DMSO-d₆: 1.78 (3H, s), 1.87 (2H, br), 2.00(3H, s), 2.39 (2H, br), 3.33 (2H, br), 3.75 (6H, br), 3.85 (2H, t, J =5.4 Hz), 4.36 (2H, t, J = 5.4 Hz), 4.80-4.94 (2H, m), 6.58-6.73 (2H, m),7.00-7.14 (5H, m), 8.59 (1H, s), 12.0 (1H, s). [FAB+]: 604 165NMR-DMSO-d₆: 1.80-2.10 (5H, m), 2.30-2.50 (2H, m), 2.70 (3H, s), 2.92(3H, s), 3.30-3.61 (10H, m), 3.75 (6H, s), 4.58 (1H, t, J = 5.3 Hz),4.65-4.93 (2H, m), 6.55-7.30 (7H, m), 10.91 (1H, brs). [ESI+]: 649 166NMR-DMSO-d₆: 2.04-2.16 (5H, m), 2.48-2.65 (2H, m), 2.87 (3H, s), 3.53(2H, br), 3.91 (6H, s), 4.04-4.08 (2H, m), 4.27-4.31 (2H, m), 4.53-4.58(1H, m), 5.00 (2H, br), 5.93-5.95 (1H, m), 6.76 (2H, br), 7.16-7.34 (5H,m), 11.09 (1H, br). [ESI+]: 603 167 NMR-DMSO-d₆: 1.87 (2H, br), 2.00(3H, s), 2.39 (2H, br), 3.20 (2H, br), 3.47 (2H, br), 3.74 (8H, br),4.78-4.92 (2H, m), 6.58-6.76 (2H, m), 7.01-7.14 (5H, m), 8.32 (1H, s).[ESI+]: 562 168 [FAB+]: 573 169 NMR-DMSO-d₆: 1.87 (2H, br), 2.00 (3H,s), 2.36 (2H, br), 2.91 (3H, s), 3.30-3.46 (5H, m), 3.56 (2H, d, J = 5.9Hz), 3.74 (6H, s), 4.91 (2H, br), 6.61 (2H, br), 7.03-7.19 (5H, m), 8.49(1H, s), 11.4 (1H, br). [ESI+]: 591 170 NMR-DMSO-d₆: 1.11 (3H, t, J =3.1 Hz), 1.87 (2H, br), 2.00 (3H, s), 2.40 (2H, br), 3.36-3.45 (6H, m),3.54-3.57 (2H, m), 3.74 (6H, s), 4.91 (2H, br), 6.61 (2H, br), 7.02-7.19(5H, m), 8.53 (1H, s), 11.5 (1H, br). [ESI+]: 605 mp: 127-129° C. 171NMR-DMSO-d₆: 1.87 (2H, br), 2.01 (3H, s), 2.37 (2H, br), 2.70 (3H, s),3.35 (2H, br), 3.41-3.44 (4H, m), 3.58 (4H, br), 3.75 (6H, s), 4.84-4.96(2H, br), 6.60 (2H, br), 7.01-7.18 (5H, m), 11.1 (1H, s). [FAB+]: 635

TABLE 132 Ex Data 172 NMR-DMSO-d₆: 1.65-1.72 (2H, m), 1.87 (2H, br),2.01 (3H, s), 2.37 (2H, br), 2.68 (3H, s), 2.89 (3H, s), 3.30-3.44 (6H,m), 3.75 (6H, s), 4.83 (2H, br), 6.60 (2H, br), 7.01-7.19 (5H, m), 8.58(1H, s), 10.9 (1H, br). [ESI+]: 619 173 NMR-DMSO-d₆: 1.88 (2H, br), 2.00(3H, s), 2.42 (2H, br), 3.39 (2H, m), 3.75 (6H, s), 4.92 (2H, br), 6.61(2H, m), 7.02-7.19 (5H, m), 8.60 (1H, s), 9.33 (1H, s), 9.77 (1H, s),11.7 (1H, s). [ESI+]: 549 174 NMR-DMSO-d₆: 1.87 (2H, br), 2.01 (3H, s),2.41 (2H, br), 2.70 (3H, s), 3.04 (2H, br), 3.42 (2H, br), 3.75 (6H, s),4.85 (2H, br), 6.59 (2H, br), 6.93-7.18 (5H, m), 10.4 (1H, s), 11.8 (1H,br). [ESI+]: 577 175 NMR-DMSO-d₆: 1.21 (3H, d, J = 6.3 Hz), 1.88 (2H,br), 2.00 (3H, s), 2.42 (2H, br), 3.36-3.66 (4H, m), 3.74 (6H, s),4.11-4.19 (1H, m), 4.91-5.05 (2H, m), 6.61 (2H, br), 7.01-7.19 (5H, m),8.59 (1H, s), 11.5 (1H, s). [ESI+]: 576 176 NMR-DMSO-d₆: 1.34-1.77 (2H,m), 2.31-2.42 (2H, m), 2.68 (3H, s), 3.26-3.32 (2H, m), 3.73 (3H, s),4.62-4.85 (2H, m), 5.23-5.81 (2H, m), 6.86-7.29 (9H, m), 7.58 (2H, br),10.7 (1H, s). [ESI+]: 533 mp: 120-121° C. 177 [ESI+]: 532 178NMR-DMSO-d₆: 1.84 (2H, br), 2.37 (2H, br), 2.70 (3H, s), 2.92 (3H, s),3.32-3.35 (4H, m), 3.56 (2H, br), 3.75 (6H, s), 4.70-4.99 (2H, m),6.47-6.55 (3H, m), 7.00 (1H, br), 7.18-7.29 (4H, m), 8.60 (1H, s), 11.0(1H, s). [ESI+]: 591 179 [ESI+]: 572 180 [ESI+]: 589 181 [ESI+]: 585 182[ESI+]: 550 183 [ESI+]: 587 184 [ESI+]: 592, 594 185 [ESI+]: 592, 594186 [ESI+]: 611

TABLE 133 Ex Data 187 [ESI+]: 590 188 [ESI+]: 573 189 [ESI+]: 572 190[ESI+]: 589 191 [ESI+]: 570 192 [ESI+]: 546 193 [ESI+]: 596 194 [ESI+]:604 195 [ESI+]: 544 196 [ESI+]: 601 197 [ESI+]: 575 198 [ESI+]: 547 199[ESI+]: 578, 580 200 [ESI+]: 576 NMR-DMSO-d₆: 1.26-1.28 (4H, m),1.41-1.48 (2H, m), 2.15 (3H, s), 2.24 (2H, m), 2.63 (1H, m), 2.69 (3H,s), 2.87 (6H, s), 3.35 (1H, m), 3.77 (3H, s), 4.73-4.78 (2H, m),5.72-5.95 (2H, m), 7.16-7.35 (2H, m), 8.18 (1H, m), 10.9 (1H, br). 201[ESI+]: 548 202 [ESI+]: 589 203 [ESI+]: 611 204 [ESI+]: 591 205 [ESI+]:589 206 [ESI+]: 585 207 [ESI+]: 589 208 [ESI+]: 590 NMR-DMSO-d₆:1.23-1.31 (4H, m), 1.41-1.49 (2H, m), 2.20-2.28 (2H, m), 2.68 (3H, s),2.87 (6H, s), 3.31-3.39 (2H, m), 3.79 (3H, s), 4.71-4.80 (2H, m),6.73-6.80 (2H, m), 6.92-7.36 (4H, m), 8.19 (1H, br), 10.85 (1H, br). mp:114-115° C. 209 [ESI+]: 586 210 [ESI+]: 590 211 [ESI+]: 606 212 [ESI+]:589

TABLE 134 Ex Data 213 [ESI+]: 561 214 [ESI+]: 597 215 [ESI+]: 578 216[ESI+]: 550 217 [ESI+]: 562 218 [ESI+]: 622 219 [ESI+]: 596, 598 220[ESI+]: 568 221 [ESI+]: 562 NMR-DMSO-d₆: 1.26-1.28 (4H, m), 1.43-1.49(2H, m), 2.28 (2H, m), 2.63 (1H, m), 2.69 (3H, s), 2.87 (6H, s), 3.35(1H, m), 3.79 (3H, s), 4.73-4.77 (2H, m), 5.87-6.34 (2H, m), 7.16-7.49(2H, m), 8.15 (1H, m), 10.8 (1H, br). mp: 112-113° C. 222 [ESI+]: 562223 [ESI+]: 658 224 [ESI+]: 600 225 [ESI+]: 540 226 [ESI+]: 512 227[ESI+]: 576 228 [ESI+]: 604 229 [ESI+]: 580 230 [ESI+]: 577 231 [ESI+]:549 232 [ESI+]: 578 233 [ESI+]: 561 234 [ESI+]: 612 235 [ESI+]: 596 236[ESI+]: 612 237 [ESI+]: 598 238 [ESI+]: 532 239 [ESI+]: 546 240 [ESI+]:615 241 [ESI+]: 633 242 [ESI+]: 647

TABLE 135 Ex Data 243 [ESI+]: 618 244 [ESI+]: 565 245 [ESI+]: 533 246[ESI+]: 591 247 [ESI+]: 534 248 [ESI+]: 533 249 [ESI+]: 592 250 [ESI+]:579 251 [ESI+]: 609 252 [ESI+]: 551 253 [ESI+]: 579 254 [ESI+]: 609 255[ESI+]: 547 NMR-DMSO-d₆: 1.32-1.77 (2H, m), 2.28-2.42 (2H, m), 2.52-2.56(3H, s), 2.65-2.67 (3H, m), 3.27-3.34 (2H, m), 3.72-3.73 (3H, m),4.62-4.86 (2H, m), 5.24-5.82 (2H, m), 6.85-6.91 (2H, m), 7.04-7.29 (7H,m), 7.63 (1H, br), 10.73 (1H, br). 256 [ESI+]: 567 NMR-DMSO-d₆:1.40-1.82 (2H, m), 2.55-2.73 (5H, m), 2.86-2.87 (6H, m), 3.33-3.39 (2H,m), 3.73 (3H, s), 4.63-4.87 (2H, m), 5.28-5.85 (2H, m), 6.73-6.94 (4H,m), 7.20-7.31 (3H, m), 10.79 (1H, br). mp: 118-120° C. 257 [ESI+]: 538258 [ESI+]: 597 259 [ESI+]: 576 260 [ESI+]: 589 261 [ESI+]: 625, 627 262[ESI+]: 596, 598 263 [ESI+]: 607 264 [ESI+]: 576 265 [ESI+]: 596, 598

TABLE 136 Ex Data 266 [ESI+]: 546 NMR-DMSO-d₆: 1.24 (3H, t, J = 7.4 Hz),1.34-1.78 (2H, m), 2.30-2.40 (2H, m), 2.64-2.66 (3H, m), 3.35-3.50 (4H,m), 3.72-3.73 (3H, m), 4.62-4.86 (2H, m), 5.24-5.82 (2H, m), 6.86-6.90(2H, m), 7.05-7.29 (7H, m), 11.11 (1H, br). mp: 123-125° C. 267 [ESI+]:558 268 [ESI+]: 591 269 [ESI+]: 550 270 [ESI+]: 564 271 [ESI+]: 564 272[ESI+]: 552 NMR-DMSO-d₆: 1.24 (3H, t, J = 7.3 Hz), 1.43-1.82 (2H, m),2.55-2.73 (5H, m), 3.33-3.39 (2H, m), 3.44-3.51 (2H, m), 3.73 (3H, s),4.63-4.87 (2H, m), 5.28-5.85 (2H, m), 6.74-6.94 (4H, m), 7.20-7.31 (3H,m), 11.09 (1H, br). mp: 124-126° C. 273 [ESI+]: 576 274 [ESI+]: 550 275[ESI+]: 550 276 [ESI+]: 585 277 [ESI+]: 550 NMR-DMSO-d₆: 1.22-1.81 (2H,m), 2.33-2.40 (2H, m), 2.66-2.68 (3H, m), 3.33-3.41 (5H, m), 3.74-3.76(3H, m), 4.66-4.89 (2H, m), 5.50-5.86 (2H, m), 6.71-6.85 (2H, m),7.05-7.31 (6H, m), 11.11 (1H, br). mp: 121-123° C. 278 [ESI+]: 564NMR-DMSO-d₆: 1.24 (3H, t, J = 7.3 Hz), 1.32-1.80 (2H, m), 2.32-2.40 (2H,m), 2.65-2.67 (3H, m), 3.32-3.50 (4H, m), 3.74-3.76 (3H, m), 4.66-4.90(2H, m), 5.50-5.86 (2H, m), 6.71-6.85 (2H, m), 7.04-7.33 (6H, m), 11.10(1H, br). mp: 111-112° C. 279 [ESI+]: 633 280 [ESI+]: 610, 612 281[ESI+]: 560

TABLE 137 Ex Data 282 [ESI+]: 565 283 [ESI+]: 553 NMR-DMSO-d₆: 1.43-1.82(2H, m), 2.52-2.73 (8H, m), 3.29-3.38 (2H, m), 3.73 (3H, s), 4.61-4.87(2H, m), 5.28-5.84 (2H, m), 6.73-6.93 (4H, m), 7.20-7.31 (3H, m), 7.62(1H, br), 10.70 (1H, br). mp: 106-109° C. 284 [ESI+]: 565 NMR-DMSO-d₆:1.33-1.82 (2H, m), 2.32-2.42 (2H, m), 2.53 (3H, s), 2.68 (3H, s),3.34-3.42 (2H, m), 3.74-3.76 (3H, m), 4.64-4.92 (2H, m), 5.50-5.87 (2H,m), 6.69-6.86 (2H, m), 7.02-7.32 (6H, m), 7.62 (1H, br), 10.71 (1H, br).285 [ESI+]: 560 NMR-DMSO-d₆: 1.30 (6H, d, J = 6.8 Hz), 1.35-1.76 (2H,m), 2.28-2.42 (2H, m), 2.63-2.65 (3H, m), 3.26-3.34 (2H, m), 3.72-3.81(4H, m), 4.63-4.86 (2H, m), 5.24-5.83 (2H, m), 6.85-6.90 (2H, m),7.04-7.29 (7H, m), 11.09 (1H, br). mp: 137-138° C. 286 [ESI+]: 607 287[ESI+]: 532 288 [ESI+]: 601 289 [ESI+]: 563 290 [ESI+]: 561 NMR-DMSO-d₆:1.32-1.78 (2H, m), 2.30-2.42 (2H, m), 2.73-2.65 (3H, m), 2.86-2.88 (6H,m), 3.27-3.32 (2H, m), 3.72-3.73 (3H, m), 4.62-4.86 (2H, m), 5.24-5.83(2H, m), 6.86-6.90 (2H, m), 7.04-7.29 (7H, m), 10.82 (1H, br). mp:110-112° C. 291 [ESI+]: 562 292 [ESI+]: 575 293 [ESI+]: 581, 583 294[ESI+]: 552, 554 295 [ESI+]: 595, 597 296 [ESI+]: 592 297 [ESI+]: 576298 [ESI+]: 612, 614 299 [ESI+]: 650, 652

TABLE 138 Ex Data 300 [ESI+]: 606, 608 301 [ESI+]: 628 302 [ESI+]: 576303 [ESI+]: 590 304 [ESI+]: 590 305 [ESI+]: 612 306 [ESI+]: 561NMR-DMSO-d₆: 1.01 (3H, t, J = 7.2), 1.86 (2H, br), 2.00 (3H, s),2.32-2.64 (2H, m), 2.69-2.79 (2H, m), 3.28-3.51 (2H, br), 3.74 (6H, s),4.66-4.97 (2H, m), 5.50 (1H, br), 6.51-6.85 (2H, m), 6.94-7.35 (5H, m),7.83 (1H, s). mp: 203-205° C. 307 [ESI+]: 576 NMR-DMSO-d₆: 1.26-1.28(4H, m), 1.41-1.48 (2H, m), 2.15 (3H, s), 2.19-2.26 (2H, m), 2.58 (6H,s), 2.60 (3H, s), 3.25-3.32 (2H, m), 3.78 (3H, s), 4.68 (2H, br),5.72-5.96 (2H, m), 7.31-7.42 (2H, m), 8.15 (1H, br). 308 [ESI+]: 590NMR-DMSO-d₆: 1.21-1.31 (4H, m), 1.40-1.49 (2H, m), 2.22-2.29 (2H, m),2.58 (6H, s), 2.62 (3H, s), 3.23-3.29 (2H, m), 3.79 (3H, s), 6.76-6.82(2H, m), 6.92-7.06 (1H, m), 7.19-7.41 (3H, m), 8.16 (1H, br). mp:219-221° C.

INDUSTRIAL APPLICABILITY

The compound of the formula (I) or a salt thereof has an antagonisticaction against LPA receptor and can be used as an agent for preventingand/or treating diseases caused by LPA.

1. A compound of the formula (I) or a salt thereof:

(wherein A is aryl which may be substituted or a hetero ring group whichmay be substituted, B is a 5-membered aromatic hetero ring group whichmay be substituted, X is a single bond or —(CR^(X1)R^(X2))_(n)—, n is 1,2, 3, or 4, R^(X1) and R^(X2) are the same as or different from eachother, and are H, halogen, OH, —O-(lower alkyl which may besubstituted), or lower alkyl which may be substituted, or R^(X1) andR^(X2) are combined with each other to form oxo (═O), or R^(X1) andR^(X2) are combined with each other to form C₂₋₅ alkylene which may besubstituted, in which when n is 2, 3, or 4, R^(X1) may be combined withadjacent R^(X1) to form a new bond, Y¹, Y², Y³, Y⁴, and Y⁵ are the sameas or different from each other, and are CR^(Y) or N, R^(Y)'s are thesame as or different from each other, and are H, OH, halogen, —O-(loweralkyl which may be substituted), —S-(lower alkyl which may besubstituted), lower alkyl which may be substituted, lower alkenyl whichmay be substituted, or cycloalkyl which may be substituted, R¹ and R²are the same as or different from each other, and are H, halogen,—O-(lower alkyl which may be substituted), or lower alkyl which may besubstituted, m is 1, 2, or 3, R³ is H, or lower alkyl which may besubstituted, R⁴ is lower alkyl which may be substituted, lower alkenylwhich may be substituted, cycloalkyl which may be substituted, arylwhich may be substituted, a hetero ring group which may be substituted,or NR¹⁰¹R¹⁰², or R³ and R⁴ may be combined with each other to form C₂₋₅alkylene which may be substituted, and R¹⁰¹ and R¹⁰² are the same as ordifferent from each other, and are H, OH, —O-(lower alkyl which may besubstituted), —C(═O)-(lower alkyl which may be substituted),—C(═O)—O-(lower alkyl which may be substituted), —NH—C(═O)-(lower alkylwhich may be substituted), lower alkyl which may be substituted, loweralkenyl which may be substituted, cycloalkyl which may be substituted,aryl which may be substituted, or a hetero ring group which may besubstituted, or R¹⁰¹ and R¹⁰² may be combined with nitrogen atoms towhich they are bonded to form nitrogen-containing monocyclic saturatedhetero ring group, in which when R⁴ is NR¹⁰¹R¹⁰², at least one of R³,R¹⁰¹, and R¹⁰² is H.)
 2. The compound or a salt thereof according toclaim 1, wherein B is a 5-membered aromatic nitrogen-containing heteroring.
 3. The compound or a salt thereof according to claim 1, wherein Bis

L is O or S, R^(L1) is H, halogen, lower alkyl which may be substituted,lower alkenyl which may be substituted, lower alkynyl which may besubstituted, or cycloalkyl which may be substituted, and R^(L2) is H,halogen, lower alkyl which may be substituted, lower alkenyl which maybe substituted, lower alkynyl which may be substituted, or cycloalkylwhich may be substituted.
 4. The compound or a salt thereof according toclaim 1, wherein X is a single bond.
 5. The compound or a salt thereofaccording to claim 1, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, R^(X1)is H, and R^(X2) is OH.
 6. The compound or a salt thereof according toclaim 1, wherein X is —(CR^(X1)R^(X2))_(n)—, n is 1, and R^(X1) andR^(X2) are combined with each other to form ethylene.
 7. The compound ora salt thereof according to claim 1, wherein Y², Y³, Y⁴, and Y⁵ areCR^(Y), R^(Y)'s are the same as or different from each other, and are H,OH, halogen, —O-(lower alkyl which may be substituted with halogen or—O-lower alkyl), lower alkyl which may be substituted with halogen or—O-lower alkyl, or cycloalkyl which may be substituted with halogen or—O-lower alkyl, and Y¹ is N.
 8. The compound or a salt thereof accordingto claim 1, wherein Y², Y³, Y⁴, and Y⁵ are CR^(Y), R^(Y)'s are the sameas or different from each other, and are H, or —O-(lower alkyl), and Y¹is N.
 9. The compound or a salt thereof according to claim 1, whereinY¹, Y³, Y⁴, and Y⁵ are CR^(Y), and are the same as or different fromeach other, R^(Y)'s are H, OH, halogen, —O-(lower alkyl which may besubstituted with halogen or —O-lower alkyl), lower alkyl which may besubstituted with halogen or —O-lower alkyl, or cycloalkyl which may besubstituted with halogen or —O-lower alkyl, and Y² is N.
 10. Thecompound or a salt thereof according to claim 1, wherein Y¹, Y², Y³, Y⁴,and Y⁵ are CR^(Y), and R^(Y)'s are the same as or different from eachother, and are H, OH, halogen, —O-(lower alkyl which may be substitutedwith halogen or —O-lower alkyl), lower alkyl which may be substitutedwith halogen or —O-lower alkyl, or cycloalkyl which may be substitutedwith halogen or —O-lower alkyl.
 11. The compound or a salt thereofaccording to claim 1, wherein Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(Y), andR^(Y)'s are the same as or different from each other, and are H, loweralkyl, or —O-(lower alkyl).
 12. The compound, wherein R⁴ is lower alkylwhich may be substituted, cycloalkyl which may be substituted, arylwhich may be substituted, a nitrogen-containing hetero ring group whichmay be substituted, or NR¹⁰¹R¹⁰².
 13. The compound or a salt thereofaccording to claim 1, wherein R⁴ is lower alkyl (in which the loweralkyl may be substituted with halogen, OH, or —O—C(O)-lower alkyl),cycloalkyl which may be substituted with a group selected from Group G¹,aryl which may be substituted with a group selected from Group G¹, or a5-membered nitrogen-containing hetero ring group which may besubstituted with a group selected from Group G¹, in which Group G¹ ishalogen, OH, lower alkyl, or —O—C(O)-lower alkyl.
 14. The compound or asalt thereof according to claim 1, wherein R⁴ is methyl which may besubstituted with halogen, ethyl (in which ethyl may be substituted withhalogen, OH, or —O—C(O)-lower alkyl), propyl which may be substitutedwith OH, oxazole which may be substituted with lower alkyl, imidazolewhich may be substituted with lower alkyl, isopropyl, cyclopropyl, orphenyl.
 15. The compound or a salt thereof according to claim 1, whereinR⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² is H, O-(lower alkyl which may besubstituted), lower alkyl which may be substituted, —C(═O)—O-(loweralkyl which may be substituted), a hetero ring group which may besubstituted, or lower alkenyl which may be substituted.
 16. The compoundor a salt thereof according to claim 1, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ isH, and R¹⁰² is H, O-(lower alkyl which may be substituted with halogen),lower alkyl (in which the lower alkyl may be substituted with halogen,OH, S-lower alkyl, or a hetero ring group), —C(═O)—O-(lower alkyl whichmay be substituted with aryl), a hetero ring group which may besubstituted with lower alkyl, or lower alkenyl.
 17. The compound or asalt thereof according to claim 1, wherein R⁴ is NR¹⁰¹R¹⁰², R¹⁰¹ is H,and R¹⁰² is lower alkyl (in which the lower alkyl may be substitutedwith halogen, OH, S-lower alkyl, or a hetero ring group).
 18. Thecompound or a salt thereof according to claim 1, wherein R⁴ isNR¹⁰¹R¹⁰², R¹⁰¹ is H, and R¹⁰² is methyl which may be substituted with agroup selected from Group G², ethyl which may be substituted with agroup selected from Group G², or propyl which may be substituted with agroup selected from Group G², in which Group G² is halogen, OH, S-loweralkyl, or a hetero ring group.
 19. The compound or a salt thereof,wherein R⁴ is NR¹⁰¹R¹⁰², and R¹⁰¹ and R¹⁰² are the same as or differentfrom each other, and are lower alkyl (in which the lower alkyl may besubstituted with halogen, OH, S-lower alkyl, or a hetero ring group).20. The compound or a salt thereof, wherein R⁴ is NR¹⁰¹R¹⁰², and R¹⁰¹and R¹⁰² are the same as or different from each other, and are loweralkyl which may be substituted with halogen or OH.
 21. The compound or asalt thereof according to claim 1, wherein m is 3, and R¹ and R² are thesame as or different from each other, and are H, halogen, —O-(loweralkyl which may be substituted with halogen), or lower alkyl which maybe substituted with halogen.
 22. The compound or a salt thereofaccording to claim 1, wherein R³ is H.
 23. The compound or a saltthereof according to claim 1, which is2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-(2-thienylsulfonyl)-1,3-thiazole-4-carboxamide,3,5-dimethoxy-4-methyl-N-{[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,3-thiazol-2-yl]methyl}-N-(3-phenylpropyl)benzamide,3,5-dimethoxy-4-methyl-N-[(4-{2-[(methylsulfonyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)methyl]-N-(3-phenylpropyl)benzamide,N-{[4-(2-{[(2-hydroxyethyl)sulfonyl]amino}-2-oxoethyl)-1,3-thiazol-2-yl]methyl}-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,sodium(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)methanesulfonate,N-{[5-(2-{[(2-hydroxyethyl)sulfonyl]amino}-2-oxoethyl)-2-thienyl]methyl}-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,N-{[5-chloro-4-(2-{[(2-hydroxyethyl)sulfonyl]amino}-2-oxoethyl)-1,3-thiazol-2-yl]methyl}-3,5-dimethoxy-N-(3-phenylpropyl)benzamide,N-{[5-chloro-4-(2-{[(2-hydroxyethyl)sulfonyl]amino}-2-oxoethyl)-2-thienyl]methyl}-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,N-[3-(3-fluorophenyl)propyl]-3,5-dimethoxy-4-methyl-N-[(4-{2-[(methylsulfonyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)methyl]benzamide,4-ethyl-N-{[542-{[(2-hydroxyethyl)sulfonyl]amino}-2-oxoethyl)-2-thienyl]methyl}-3,5-dimethoxy-N-(3-phenylpropyl)benzamide,N-({4-[(acetamidesulfonyl)methyl]-1,3-thiazol-2-yl}methyl)-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,3,5-dimethoxy-4-methyl-N-[(1-{2-[(methylsulfonyl)amino]-2-oxyethyl}-1H-pyrazol-3-yl-methyl]-N-(3-phenylpropyl)benzamide,N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,N-[(4-{2-[(aminosulfonyl)amino]-1-methyl-2-oxoethyl}-1,3-thiazol-2-yl)methyl]-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,5-chloro-2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,N-[(1-{2-[(ethylsulfonyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)methyl]-N-[3-(3-fluorophenyl)propyl]-3,5-dimethoxy-4-methylbenzamide,N-[(5-{2-[(aminosulfonyl)amino]-2-oxoethyl}-2-thienyl)methyl]-3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamide,N-(aminosulfonyl)-6-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}pyridine-2-carboxamide,N-(aminosulfonyl)-5-chloro-2-{[(4-hydroxy-3,5-dimethylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-oxazol-4-carboxamide,N-(aminosulfonyl)-2-{[(4-cyclopropyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-{[(4-bromo-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,N-(acetamidesulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-5-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-2-furamide,N-(aminosulfonyl)-6-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}pyrazine-2-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(ethylamino)sulfonyl]-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-({[3-(5-chloro-2-thienyl)propyl](3,5-dimethoxy-4-methylbenzoyl)amino}methyl)-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(5-methyl-2-furyl)propyl]amino}methyl)-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(2-fluorophenyl)propyl]amino}methyl)-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-({[3-(2,5-difluorophenyl)propyl](3,5-dimethoxy-4-methylbenzoyl)amino}methyl)-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-4-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-2-carboxamide,2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,2-{[(4-ethyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(3-thienyl)propyl]amino}methyl)-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-methyl-1,3-thiazole-4-carboxamide,2-{[(4-cyclopropyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide,methyl({[(2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazol-4-yl)carbonyl]amino}sulfonyl)methylcarbamate,N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-methyl-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-fluoroethyl)(methyl)amino]sulfonyl}-5-methyl-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(pyridin-2-ylamino)sulfonyl]-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[ethyl(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-[(methoxyamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-{[(2-fluoroethyl)(2-hydroxyethyl)amino]sulfonyl}-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,2-({[(2,4-dimethoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[(dimethylamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(2-hydroxypropyl)sulfonyl]-1,3-thiazole-4-carboxamide,2-({[3,5-dimethoxy-4-(methoxymethyl)benzoyl](3-phenylpropyl)amino}methyl)-N-[(methoxyamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide,2-({(3,5-dimethoxy-4-methylbenzoyl)[3-(2-fluorophenyl)propyl]amino}methyl)-N-[(dimethylamino)sulfonyl]-1,3-thiazole-4-carboxamide,2-({[hydroxy(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-N-(methylsulfonyl)-1,3-thiazole-4-carboxamide,N-aminosulfonyl)-2-({[hydroxy(4-methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide,N-[(dimethylamino)sulfonyl]-2-({[(2-fluoro-4-methoxyphenyl)(hydroxy)acetyl](3-phenylpropyl)amino}methyl)-5-methyl1-1,3-thiazole-4-carboxamide,N-[(dimethylamino)sulfonyl]-2-({[hydroxy(6-methoxypyridin-3-yl)acetyl1](3-phenylpropyl)amino}methyl)-5-methyl-1,3-thiazole-4-carboxamide, orN-(dimethylsulfamoyl)-2-{[{[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl}(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxamide.24. A pharmaceutical composition comprising the compound or a saltthereof according to claim 1 and a pharmaceutically acceptableexcipient.
 25. A pharmaceutical composition for preventing and/ortreating diseases caused by LPA, comprising the compound or a saltthereof according to claim
 1. 26. Use of the compound or a salt thereofaccording to claim 1 for the preparation of a pharmaceutical compositionfor preventing and/or treating diseases caused by LPA.
 27. Use of thecompound or a salt thereof according to claim 1 for preventing and/ortreating diseases caused by LPA.
 28. A method for preventing and/ortreating diseases caused by LPA, comprising administering to a patientan effective amount of the compound or a salt thereof according toclaim
 1. 29. The compound of the formula (I) or a salt thereof forpreventing and/or treating diseases caused by LPA.